Note

Development of an innovative delivery system forbacillus Calmette-Guérin bladder administration
Michael t. Szewczyk Jr, PharmD,
BCoP, Waterford Care Center, Yale New
Haven Health Smilow Cancer Hospital,
Waterford, CT
Scott A. Soefje, PharmD, MBA,
BCoP, FCCP, FHoPA, Mayo Clinic,
Rochester, MN, and Mayo Clinic Collegeof Medicine and Science, Rochester, MN

Purpose. To describe the development of an innovative process to deliver
bacillus Calmette-Guérin (BCG) to an offsite urology clinic for bladder instillation.

Conclusion. The use of the CSTD allowed the patients to continue to receive bladder instillations at an offsite urology clinic without signifcantly
disrupting compounding workfow at the small infusion center pharmacy
that was the nearest to the clinic.
Keywords: BCG, bladder cancer, bladder instillation, closed-systemtransfer device, infusion center, urology clinic
Am J Health-Syst Pharm. 2020;78:60-64

T

Address correspondence to Dr. Soefje(Soefje.Scott@mayo.edu).
Twitter: @sasoefje© American Society of Health-System
Pharmacists 2020. All rights reserved.
For permissions, please e-mail: journals.
permissions@oup.com.
DOI 10.1093/ajhp/zxaa339

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AM J HeALtH-SYSt PHARM |he use of bacillus Calmette-Guérin(BCG), a live virus vaccine for treatment for recurrent tumors in patientswith localized cancer of the urinary
bladder, has created many logisticalproblems for hospitals and infusion
center pharmacies. Te virus has ashort stability, 2 hours from reconstitution, and requires special handlingfor preparation and administration.
Cross contamination of the virus withother preparations has been reported,
necessitating extra precautions when
preparing the virus.1 Te use of biological safety cabinets is necessary,and the cabinets require decontamination and cleaning after each BCG
preparation session, a process thatis time consuming and can be problematic in a busy infusion center withlimited hood space for intravenous (IV)
medication preparation.
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Problem
At a large academic medical center,the urology services were geographically expanding as the institution acquired new clinics and integrated theminto its cancer center. Te practices
had been providing, and wanted tocontinue to provide, BCG treatments,
creating logistical problems for thepharmacy. A solution was needed inorder to meet the safety requirementsof BCG product preparation and delivery to patients within the limited
timeframe of BCG stability.
For many of the medical center’surology clinics, the drug was being
prepared in the main hospital’s oncology pharmacy and delivered to theclinic site, typically just a few foors ora few blocks away. However, one of theurology clinics was located morethan 20 miles from the main hospital

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Summary. The use of BCG, a live virus vaccine for treatment of patients with localized cancer of the urinary bladder, has created manylogistical problems for hospitals and infusion center pharmacies. Dueto its short stability, the drug cannot be made ahead of time and coordination with a patient’s arrival at an infusion site is challenging. This
becomes exceptionally challenging when a urology clinic has limited
compounding capacity and/or is distant from the site of BCG medication preparation. This article describes an innovative process involving
use of closed-system transfer devices (CSTDs) to allow for the administration of BCG in a urology clinic offsite from a medical center’s infusion
center facilities.

Note

INNOVATIVE INTRAVESICAL DELIVERY SYSTEM

Solution
In discussions of potential solutions, the frst thoughts were to use aninfusion container system such as the

KeY PoINtS• Bladder instillations of bacillus
Calmette-Guérin (BCG) entail
a complex process that posessignifcant logistical challenges
for any cancer infusion center.

Figure 1. Process for mixing bacillus
Calmette-Guérin (BCG) preparations
prior to the process change. CTSD
indicates closed-system transfer device; RN, registered nurse.

Place BCG vial and adaptor in
CSTD clamp and spike vial

• Urology clinics that have limited
compounding capacity and/or are located a signifcant distance from an infusion centerare limited in their ability toprovide BCG bladder instillation
services due to safety concerns
related to the drug’s shortstability timeframe.

Draw up required diluent withsyringe/needle

Remove needle and attachsyringe connector
Attach syringe connector to vial
adaptor, open connection, andreconstitute BCG• An innovative new process
involving use of a closedsystem transfer device wasdeveloped to overcome thelogistic challenges of BCG administration in an offsite urology
clinic.

Close connection and remove
syringe connector from vial

Draw required final product diluent
into a 60-mL syringe with a needle

Remove needle and attach a newsyringe connector

Attach syringe connector to vial

Mini-Bag Plus (Baxter, Deerfeld, IL) or
ADD-Vantage system (Pfzer Inc., New
York, NY). Te problem was that BCG
vials have an 11-mm top and none of thecommercial systems at the time could
handle the small vial size or, at least,
handle it in a manner that would not
introduce the possibility of exposing the
preparer to BCG. One CSTD company
ofered a process to handle BCG, andwe were already using that company’s
device; however, that process was forsyringes only and required that the drug
be already reconstituted and would notallow for transport over the distances
required. Te ideal solution was to fnd
a process that would allow bedside activation of the vial while maintaining aclosed environment. We worked with a
medical device company (ICU Medical,
San Clemente, CA), pharmacy technicians in the oncology pharmacy,
pharmacists, and the urology clinic todevelop, test, and evaluate a potential
new device kit that might help overcome
the BCG challenges. A second goal was
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Open connection and draw
contents of vial into syringe
Close connection and disconnect
syringe connector from vial
adaptorCap syringe connector anddispense to RN

to fnd a system that would maintain, if
not improve, the efciency of preparation while maintaining the safety standards and minimizing possible exposure.
New process. Te solution developed included changing the delivery
system from a syringe to an IV piggyback bag (50 mL) and creating a CSTD
system process that would allow for the
setup of the BCG vial in the pharmacy
without reconstitution, allow for transport of the infusion setup (with the
CSTD attached) to the urology clinic,
and provide a process for BCG activation at the bedside, thereby delaying the
2-hour expiration window—all in a contained environment. Te new process|

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in an area that often had signifcant
trafc issues. Given the 2-hour stability of reconstituted BCG, the pharmacy was faced with limited options.
Te distance from the main hospitalprohibited the mixing of BCG in thehospital’s outpatient infusion pharmacy because of the challenge ofconsistently meeting the time requirements. A closer infusion pharmacy wasavailable; however, that pharmacy wasin a busy practice and only had one
biological safety cabinet. Taking thatcabinet out of service for cleaning anddecontamination during the middleof the day would create signifcant
burdens in terms of meeting the treatment needs of the cancer patients inthat center. Te pharmacy needed a
new solution for delivery of BCG thatwould allow for advance preparation of
the product without signifcant downtime for the IV hood. We began to look
for a solution that would allow us tomeet the needs of our patients whileallowing them to stay at the remoteurology center and, at the same time,
meeting required regulatory standards.
Te BCG preparation process inplace at the time of the problem is outlined in Figure 1. Te 11-step process
involved placing reconstituted BCG ina syringe with a closed-system transfer
device (CSTD), a drug transfer device
attached via an adaptor to the end ofa syringe that mechanically prohibits
the transfer of environmental contaminants into a system and the escape of
hazardous drug or vapor concentrations
outside the system.2 Once the BCG preparations for the day were mixed, thehood was cleaned and decontaminatedand removed from use for at least 30 minutes. Intrathecal (IT) medications were
never mixed in this hood (that prohibition served as an added precautionary
measure), but the organization had theluxury of 6 hoods in total, so excluding
this particular hood from use in preparation of IT medications was easy.

Note

INNOVATIVE INTRAVESICAL DELIVERY SYSTEM

is outlined in Figure 2, and the systemcomponents are pictured in Figure 3.
Te process steps are as follows.

Te largest part of the time savings achieved through use of the newprocess resulted from pharmacy technicians preparing all of a day’s BCG
doses at once in the biologic safety cabinet. We still decontaminated the hood;
however, the technician had to do thisprocedure only once a day, usually
early in the morning before the infusionclinic became busy.
testing for contamination. Terewas still concern that the activation of
the bags in the IV hood could create apossibility of BCG contamination, so
clinical epidemiology personnel were
contacted to test the hoods for contamination. A pharmacy technician cleaned
and decontaminated the IV hood as per
the usual process, then prepared a doseof BCG using the new methodology. Te

Figure 3. Components of the kits developed by ICU Medical to accommodate
a new process for mixing bacillus Calmette-Guérin preparations that involves
use of its ChemoClave and ChemoLock closed-system transfer devices. Kit#CH3507 is a ChemoClave-based system, and Kit #CL3927 is a ChemoLockbased system. Photos courtesy of and used with permission of ICU Medical,
San Clemente, CA.

Kit #CH3507(ChemoClave)

Figure 2. New process for mixing
bacillus Calmette-Guérin (BCG)
preparrations. CTSD indicates closedsystem transfer device; RN, registerednurse.

..

Spike bag with bag spike
adaptor and clamp
tubingi

Bag Spike Adaptor

Spike vial with vial
adaptorAttach the vial adaptor toto the bag spike adaptor
at the CSTD end

RN activates vial
immediately prior toadministration

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AM J HeALtH-SYSt PHARM |Kit #CL3927(Chemolock)

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Urinary Catheter
Adaptor

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Step 1. Te pharmacy technician attaches a
CSTD bag spike adaptor with tubing(Figure 3) to the IV piggyback bag andclamps the tubing.
Step 2. A second CSTD vial adaptor (Figure 3)
is placed on the BCG vial, and the 2adaptors are connected to the opposite
end of the tubing (Figure 4, panel A).
Te vial can be removed at the CSTD
adaptor between the vial and thetubing. Tis setup can be delivered
to the urology clinic in a zip-lockedchemotherapy bag.
Step 3. At the appropriate time, a nurse removes the setup from the delivery bag
and unclamps the tubing, creating
an open connection between the IV
bag and vial. Te nurse then gently
squeezes the IV bag, forcing fuid in
the vial to reconstitute the BCG. Aftera short time to allow the powder to dissolve, the nurse then inverts the systemand squeezes air into the vial, which
forces the reconstituted BCG into thebag. Te tubing is then clamped.

Step 4. The vial is disconnected from the IV
bag at the CSTD adaptor; this maintains a closed environment. Te vial isdisposed of in a biohazard container.
Step 5. Te remaining IV bag with the mixed
BCG has a CSTD adaptor and can be
attached to the adaptor tubing, which
is designed to deliver the solution to
the bladder through a urinary catheter(Figure 4, panel B). Te nurse inserts theurinary catheter adaptor into the urinary
catheter and then attaches the BCG tothe adaptor at the CSTD end. Te nurse
then opens the clamps, allowing the
BCG to fow into the bladder by gravity.

Note

INNOVATIVE INTRAVESICAL DELIVERY SYSTEM

Figure 4. Setup for bladder instillation of bacillus Calmette-Guérin as it looks
when ready for dispensing from the pharmacy (panel A) and as it appears
with urinary catheter adaptor attached (panel B), just prior to administration.
A sample medication vial used for training purposes and the ChemoLockclosed-system transfer device (ICU Medical, San Clemente, CA) are shown.
Photos courtesy of and used with permission of ICU Medical.

AB

6-hour beyond-use date. Any unused
doses are returned to the pharmacy to
be properly disposed of at the end of
the day or after a patient has left theclinic. Tis can be a problem in a timeof shortage, so balancing the number ofdoses prepared in advance with thosepotentially wasted is a challenge.

Discussion

system can be set up in advance anddelivered to the urology clinic for activation. Te preparation time for the 2diferent processes was measured, andpharmacy technician time was reducedby the new process (Figure 5). While thereduction in technician time for eachdose is minimal, the new process provides major cumulative time savings,
in that the chemotherapy hood is onlyused once per day, generally at the very
beginning of the day, and is decontaminated once a day, thereby obviating theneed to take the hood out of service
multiple times per day. In a site witha single chemotherapy hood, this is asignifcant advantage. Once connectedin the IV hood, the setup is assigned a
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epidemiology department sampled thehood for surface and airborne contamination and tested for growth of BCG.
No growth of BCG was detected.
One rationale for the new process
was that BCG preparation could be
handled by the nearest oncology infusion center, without the need to take an
IV hood out of service for an extended
time; and although that is not currently
done, it is believed that the vials could
be safely set up and activated in theurology clinic at the bedside.
Day-to-day process. Under the
new process, the oncology pharmacies get a list of all patients due to receive BCG on a given day at one of theurology clinics. Te BCG administration

Working with a CSTD device company, the cancer center developed aprocess to set up BCG in the pharmacy
without reconstituting the vial. Tis process allowed for safe transport of the vial
to a distant urology clinic for onsite activation and use. Te process provided
a safe setup method without exposing
a pharmacy technician to BCG, as demonstrated by the lack of BCG detected in
the IV hood. Tis process was used successfully and led ICU Medical to develop
2 kits (one version compatible with its
ChemoClave CSTD and the other compatible with its ChemoLock CSTD; see
Figure 3) for use with BCG preparations.
Tis new process allows BCG activation
at the bedside, thereby allowing pharmacy personnel to prepare the medication in advance without the limitationof the 2-hour stability. At our facility
this process worked only when full vials
were used to prepare a dose; any partial
doses still had to be mixed according
to conventional methods. Tis process
dramatically improved the workfow of
oncology infusion centers in providing
BCG infusions to urology clinic patients
while also maintaining safety.
Given the closed nature of the process, it is felt that the process could beapplied in the urology clinics. Te vials,
IV bags, and CSTD kit required for BCG
administration could be stored in an
automated dispensing cabinet, and anurse could activate the product justprior to use; this would be similar to
the activation of IV products using the
ADD-Vantage, Mini-Bag Plus, or similarsystems. Te simplicity of the method
developed might allow other CSTD
companies to develop similar kits.
One consideration in potential
implementation of the new process
is the efect of sterile compoundingNote

INNOVATIVE INTRAVESICAL DELIVERY SYSTEM

Figure 5. Mean and median pharmacy technician time required to prepare adose of bacillus Calmette-Guérin for bladder instillation with use of the traditional
process (blue bars) and the new process (orange bars).

16

14

New

Process

Process

Doses

21

51

I 8

Mean

6.53 min2.95 minE

Median6.48 min2.63 min

10

'2

QJ

;::
6

Te new process allows cancer centers to meet patient needs by supplying
BCG preparations for administration in
ofsite local urology clinics in a safe andefective manner. Tis innovative process, which provides a solution to a complex problem, was developed throughcollaboration of an oncology pharmacy,a device company, and urology clinics.

4

requirements specifed in United States
Pharmacopeia (USP) general chapter
7973 and hazardous drug handling requirements specifed in USP generalchapter 800 (<USP 800>).4 We believethat if the components of the BCG delivery system are assembled under ahood but the drug is not reconstituted,
such a process might at least meet thestability standard applicable when accessing a single-dose vial, which would
give a beyond-use date of 6 hours.
Once reconstituted using the process,the stability is that of the drug: 2 hours.
From a USP <800> perspective, the assembled product would be a closed
system. Could it then be considered
to meet the standard of a conveniently
packaged product, meaning that a risk
assessment could be done and the institution could determine the personal
protection equipment required for
mixing and administering the product?
If companies would do the right studies
and submit them for Food and Drug
Administration approval, could thissystem be comparable to other systems that allow mixing on patient careunits? Even if not, imagine the beneft
if the stability of the assembled (butunreconstituted) products could be

64

Conclusion

AM J HeALtH-SYSt PHARM |multiple days or even weeks. Tis extended stability window would also
help in times of shortage by allowing
more fexibility in prepreparing doses,
which could be done with the knowledge that if doses were not used thesame day, they might be used later.
Until more is known about how regulators will view this type of innovative
solution to a complex problem, there
are more questions than answers andthus there can be no “ofcial” recommendations. Pharmacy leaders at eachpractice site will have to assess how theywould approach using this process.
BCG causes signifcant problems incompounding, especially at smaller sites
with limited chemotherapy hood capacity and sites that are far enough awaythat the 2-hour stability window limits
mixing and delivering of the drug. Even
though the new process does not yield amajor time savings per individual compound, it can yield considerable timesavings overall because of the decreased
time an IV hood is unusable due to decontamination. Since the preparations
are prepared early in the day all at once,the chemotherapy hood is only out ofservice for a single decontamination
process; this is a signifcant advantage in

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Disclosures
Te authors have declared no potential conficts of interest.

References
1. Vos MC, de Haas PEW, Verbrugh HA,
et al. Nosocomial Mycobacterium bovis–
bacille Calmette-Guérin infections due
to contamination of chemotherapeutics:
case fnding and route of transmission. J
Infect Dis. 2003;188:1332-1335.
2. National Institute for Occupational
Safety and Health, Centers for Disease
Control and Prevention. NIOSH alert
2004–165: preventing occupational
exposures to antineoplastic and otherhazardous drugs in health care settings.
http://www.cdc.gov/niosh/docs/2004–
165/pdfs/2004–165.pdf. Published 2004.
Accessed July 3, 2018.
3. United States Pharmacopeial Convention.
General chapter 797. In: United States
Pharmacopeia and National Formulary(USP 41-NF 36). https://online.uspnf.
com/uspnf/document/GUID-AC788D4190A2-4F36-A6E7-769954A9ED09_1_
en-US. Published 2016. Accessed
November 5, 2019.
4. United States Pharmacopeial Convention.
General chapter 800. In: United States
Pharmacopeia and National Formulary(USP 41-NF 36). https://online.uspnf.
com/uspnf/document/GUID-AC788D4190A2-4F36-A6E7-769954A9ED09_1_
en-US. Published 2016. Accessed
November 5, 2019.

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Traditional
12

infusion centers that have limited hoodspace and are associated with busy infusion centers and urology clinics. While a
movable glove box could provide an answer in some of these cases, at our practice site it was decided that buying a glove
box, setting it up in a urology clinic, andsending a pharmacist or pharmacy technician to the clinic for a small number ofpatients each week would be inefcientand that a more practical approach was
to use the process described here.