PRINTER-FRIENDLY VERSION AVAILABLE AT PHARMACYPRACTICENEWS.

COM

Beyond-Use Dates for Parenteral

Nutrition Must Take Compatibility
And Stability Into Consideration

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SARAH V. COGLE, PHARMD, BCCCP, BCNSP wi unle
tho ssnutrition (PN) is a

P
arenteral
Clinical Pharmacist, Burn ICU/Nutrition Support
ut admixture
oth
Department of Pharmacy, Clinical Programs complexper erw containing up
Vanderbilt University Medical Center
mi
Nashville, Tenn.
ss isafter
to 50 ingredients
e n combining
i
nutrients from at leastoeight ote
n i different
DIANA W. MULHERIN, PHARMD, BCNSP, BCCCP, FCCM
s d.
pr contain
pharmaceutical products that
Clinical Pharmacist Specialist, Nutrition Support
oh
Department of Pharmacy, Clinical Programs
ibi
Vanderbilt University Medical Center active ingredients, excipients and/or ted
materials (e.g., packaging, containers,.
Nashville, Tenn.

GORDON S. SACKS, PHARMD, BCNSP, FASPEN, FCCP infusion sets). An understanding of

Senior Director, Medical Affairs for PN Market Unit
Fresenius Kabi USA LLC pharmaceutical science allows one to
Lake Zurich, Ill.
apply known data on the physical and
JAY M. MIRTALLO, MS, RPH, FASHP, FASPEN chemical properties of substances to best
Clinical Practice Specialist
American Society for Parenteral and Enteral Nutrition
predict solubility, compatibility and stability,
Professor Emeritus formulation design and physiologic action.
The Ohio State University, College of Pharmacy
Columbus

PHARMACY PRACTICE NEWS SPECIAL EDITION • JUNE 2023 29

 It is essential for the pharmacist to review PN for com- to pH, temperature, light, oxygen, solvents and/or reac-
patibility and stability to assure it is safe to prepare and tants. Instability may result from physical reactions leading
administer. More importantly, it is imperative to consider to crystallization, adsorption or a broken/cracked lipid inject-
compatibility and stability principles of PN when determin- able emulsion (ILE) (note phases of ILE instability4). Chemical
ing its beyond-use date (BUD). This is especially critical for instability results from hydrolysis or oxidation that may occur
pharmacists to understand since the updated USP Gen- during PN preparation, storage and administration. This
eral Chapter <797> standards,1 which go into effect on Nov. involves exposure to air and/or light. Instability manifests as
1, 2023, focus mostly on sterility considerations for BUD. the appearance of particulate matter, a visible haze, a visi-
Often, the BUD for PN is shorter than that for other com- ble oil and/or color change (Table 1).
pounded sterile preparations (CSPs) The complex nature of PN from a
due to the various chemical interac- compatibility and stability standpoint
tions within the final product that, over can be explained by the various phys-
time and exposure to the environment, Compatibility and stability ical and chemical characteristics of
facilitate degradation and chemical are as important as each nutrient present in the final prod-
reactions that change the bioavailabil- sterility in determining uct (Table 2). The unique nature of
ity of the nutrients or create precipi- each nutrient creates essential vari-
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tates or byproducts that induce harm PN admixture BUDs. ables that must be considered for PN
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when infused.2 The purpose of this
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compatibility (Table 3) and PN stability

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article is to explain why it is essential (Table 4). These variables include sol-
re
se ht 2
to consider compatibility and stability, and not only sterility, ubility, pH, reactivity of a salt (especially with pH changes)
when determining the BUD for PN. and the resultant valence (especially of electrolytes). Most
rve 02 importantly, the nutrients that are vulnerable to extremes of
d. 3
PN Compatibility and Stability temperature, light and oxidation influence stability and com-
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Compatibility is the uneventful physical and chemical patibility over time. These characteristics influence the PN
pr Mc
od M
coexistence of two or more components over time after compounding process (potential to introduce air/oxygen) as

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being combined. An incompatibility is either a physical inter- well as transport, storage and environmental exposure dur-
tio on
action (complexation, leaching or desorption) or chemical ing infusion. All of these variables must be determinants of
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interaction (intermolecular or interionic reactions) between the BUD for PN.
two or more substances over time in a specific environment. Compatibility and stability considerations during each
ho lish
The incompatibility can involve active ingredients (nutrients phase of the PN care process are outlined in Table 5. These
le ing
in the case of PN), excipients and/or other materials, such are important points to ensure all compatibility and stabil-
or
in Gro
as the final container. Incompatibility in PN manifests as a ity concerns are addressed throughout the entire process:
change in color, pH, osmolality or viscosity, formation of gas, from prescribing through the completion of administration.
or the yielding of a precipitate (Table 1). pa up Compatibility and stability are as important as sterility in
rt
Stability is the maintenance of chemical integrity of
wi unle
determining PN admixture BUDs.
each active ingredient or the physical integrity of the dos- tho ss
age form/system over time in a given environment.3 Insta- ut
USP Chapter <797>
o
bility is the irreversible decomposition/degradation of active pe the
The intent of USP <797> is to serve as minimum standards
ingredients or dosage form/system as a result of exposure rm rw
for the preparation of CSPs. In these standards, CSPs are
iss ise
ion no
Table 1. Simplified Definitions of Compatibility and Stability is ted
pr .
Compatibility Incompatibility Stability Instability oh
Definition No physical or
ib
Irreversible chemical reaction occursite
d.
Physical and/ Chemical integrity
chemical reactions or chemical of all ingredients is when ingredients are combined or
occur when interaction occurs maintained in a given exposed to changes in pH, temperature,
ingredients are when ingredients environment light, oxygen, solvents and/or reactants
combined combined
Example Change in color, Physical instability from crystallization,
pH, osmolality or adsorption, broken/cracked ILE
viscosity, formation
Chemical instability from hydrolysis or
of gas, precipitate
oxidation (exposure to air and/or light):
formation
particulate formation, visible haze,
visible oil, color change

ILE, lipid injectable emulsion.

30 PHARMACYPRACTICENEWS.COM
 categorized into groups to determine their BUDs. The BUD
is defined as the date, or hour and date, after which a CSP
must not be used, stored or transported. It is determined
from the date and time the preparation is compounded.1 The
2008 version of USP <797> incorporated risk categories for
determining BUDs (immediate, low, medium and high risk)
that mainly focused on the environment in which the CSP
was prepared and number of manipulations required for
compounding.5,6 The 2022 revisions include three catego-
ries for CSPs, and place a heavier emphasis on sterility by
not only incorporating the environment in which the CSP is
compounded but also the likelihood for microbial growth dur-
ing storage and the period in which the CSP must be used.1
As previously described, maintaining sterility is key for estab-
lishing a safe BUD, but the chemical and physical stability of
CSPs must also be considered. In addition, the BUD should
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not exceed the shortest remaining expiration date of any
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component of the CSP. For example, IV multivitamins, an inte-
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gral component of PN, undergo degradation with exposure
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d. 3 Characteristics of PN
Table 2. Physical/Chemical
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Nutrient Characteristic
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Macronutrients
Amino tio onAA
• Both essential and nonessential
• Some added as chloriden salts for P
acids
in
solubility
wh at lis
• Tyrosine—low solubility, precipitates
ole hin
low pH
• Amphoteric—provide buffering capacity o
important to titratable acidity
• pH of AA solution usually dictates final
pH of admixed PN
• Stored in plastic containers—exposure to
oxygen is enhanced
Dextrose • Low pH depending on concentration,
ranges from 3.2-6.5
• 5% dextrose has a pH in the range of
4-4.5; no titratable acidity
• Concentration results in isotonic or
hypertonic formulation that may affect
compatibility
ILE • Oil-in-water emulsion—particle size
similar to chylomicron
• Inherently unstable; many factors may
reduce the effective forces of the
emulsifier
• Most stable at pH of 6-9
• PFAT5 (% of particles >5 microns in
size) <0.05% is the criteria for safe
administration
• Stages in lipid destabilization are
reversible and irreversible
• Exposure to air/oxygen results in oxidized
fatty acids causing a reduction in pH
to light and oxygen. Therefore, once diluted in the PN admix-
ture, it should be infused within 24 hours or refrigerated and
protected from light if administration is delayed.3,7 As insti-
tutions are incorporating the new <797> standards, BUDs
should be established conservatively so each drug or admix-
ture maintains sterility and stability until its BUD ends and the
drug (PN) should be discarded.
Under the 2008 standards, PN is classified as a medium-
risk CSP, because the compounding of a PN involves mul-
tiple CSP transfers into one CSP, and PNs are prepared in
an ISO class 5 environment with sterile ingredients.5,6 In the
2022 revisions, PN formulations are reclassified as Cate-
gory 2 CSPs, under the subcategory of CSPs prepared from
only sterile starting components and without sterility test-
ing of the final admixture.1 Many readers may look to Table
13 of the 2022 revisions for BUD guidance for Category 2
BUDs, but this table indicates the longest permitted BUDs
for each category.1 A BUD of four days at controlled room
temperature (CRT, 20° C to 25° C) or up to 10 days under
Nutrient Characteristic
Micronutrients
Electrolytes • Inorganic vs. organic salts: ionization, free
ub
content, difference in reactivity important
to compatibility
• Chloride salt: dissociates to a greater
gG degree than other salts, releases HCl to
r in ro
lower pH
pa up reactive
• Multivalent/divalent cations are more
rt
wi un• lCalcium
e
and phosphorus valence,
tho ss determine compatibility
reactivity
u• tMultipleooxidative
Trace
pe ttrivalent,
he states: monovalent,
elements
rm rw
divalent, solubility/stability is pH
dependent isemost physiologic
isschromic
• Chromium:
i on inncombination
available, no longer ote trace
element product inis
pr mostd.soluble
the United States
• Copper: cupric (divalent)
oh
and stable in solution
ibi zinc:
• Manganese: divalent most soluble; ted
.
very soluble in divalent form
Vitamins • 2 vials: separated for stability purposes,
combined prior to addition to PN
• Fat soluble, contain polysorbates to
facilitate dissolution
• Buffering agents used to maintain most
stable pH for storage
• Several vitamins affected by light,
oxidation and temperature
• Limits long-term stability in PN
AA, amino acid injection product; HCl, hydrochloric acid;
ILE, lipid injectable emulsion; PN, parenteral nutrition.
PHARMACY PRACTICE NEWS SPECIAL EDITION • JUNE 2023 31
refrigeration is assigned to this type of CSP, which is in
stark contrast to the 30 hours at CRT recommended in the
2008 standards1,5 (Table 6). However, this new classification
is based only on sterility, and special attention should be
given to Footnote A under Table 13 and Section 14.3, which
further describes that the BUDs in the table are based on
the risk for microbial contamination and ability to remain
sterile but that the CSP must remain chemically and physi-
cally stable, and its packaging must preserve its integrity for
the duration of the BUD.1
Applying Principles of Compatibility and Stability
Into Practice—It’s All in the Details
As illustrated in the previous sections of this article,
the pharmaceutical aspects of stability and compatibil-
ity are quite complex, and pharmacists are relied upon
for decisions relating to drug compatibility with PN. While
tertiary resources on medication compatibility are eas-
ily accessible, pharmacists must be involved in decisions
relating to medication co-infusion (e.g., y-siting) with a
PN admixture. Online resources offer the convenience of

Table 3. Compatibility Concerns With PN Table 4. Stability Concerns With PN

Nutrient Concerns Nutrients Concerns

Amino • Deamidation and deamination are

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Macronutrients
l ri Co• Maillard reaction occurs over time
acids accelerated at higher temperatures
gh
Dextrose

ts ptemperatures
• L-glutamine: oxidized to toxic byproduct
and amino
yri
and is accelerated with increasing during heat sterilization; not included in
acids
g
re• Glycosylamines
sin eaminohtacid
amino acid injection products
resulting in a decrease
2
rveproducts
02 excreted in the urine,
bioavailability • Amino acids degrade when exposed

3 elements
to light/oxygen: greater occurrence in
• Maillard
d
increased .loss of trace
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plastic vs. glass containers

ro Mofcinto
• Photo-oxidation occurs with several
psystem amino acids and can be enhanced in the
M
ILE • Changes physical the
d uc aPN;hall
final formulation if admixed presence of riboflavin

the other nutrient additivestio o

becomes an emulsion containing
ni nP
ILE • Macronutrient concentration favorable

Storage of PN should be at 4° C for compatibility, stabilitynand

ub
to stability: amino acids ≥4%, dextrose
wh lis ≥10%, ILE ≥2% (SO-ILE)
sterility
ole hin • Divalent cations influence the stability

or g G • Limit divalent cations (Mg, Ca) to

of ILE

in
Micronutrients
r
Electrolytes • Calcium and phosphorus are the most pa oup<20 mEq/L final PN concentration if ILE
rt • Exposure
wi unle to air/oxygen causes oxidation
included
problematic; to avoid precipitation,

thofofatty acids
the following factors must be known
and considered in determining their ss and reduces PN pH
solubility: ut time
− Over oincreases
the levels
the PFAT to
pe harmful
5
potentially
• PN final pH
rm rwthe degradation
ise
i s >4);
of ascorbic acids(pH
• Amino acid product Trace • Copper accelerates
• Amino acid final concentration elements i noform
oncuprous
ascorbic acid
• Dextrose final concentration reduces copper to its
i ted
s pto insoluble
ro .
• Calcium salt • Increased risk for reduction

concentrations of ascorbic acid hi

• Phosphate salt
• Temperature
• Sequence of calcium and phosphate
addition to PN
• Time of PN storage
Trace • Copper precipitates with cysteine
elements • Iron dextran not recommended to be
included in PN with ILE (TNA)
Vitamins • Vitamins may react with each other,
macronutrients, excipients or the PN
plastic final container
− Vitamin A adsorbs to plastic materials
ILE, lipid injectable emulsion; PN, parenteral nutrition;
TNA, total nutrient admixture.
selenium in the presence of high
bit
• Factors affecting vitamin stability: lighted
.
Vitamins
exposure, pH, temperature, PN final
container materials (plasticizer from bag)
− Riboflavin acts as a photosensitizer
• Folic acid insoluble at low pH; a PN pH
>5 prevents precipitation
• Thiamin is affected by sulfite
concentration, pH, temperature,
exposure to sunlight and the presence
of oxygen
Ca, calcium; ILE, lipid injectable emulsion; Mg, magnesium;
PFAT5, percentage of fat globules larger than 5 microns in
diameter; PN, parenteral nutrition; SO, soybean oil.

32 PHARMACYPRACTICENEWS.COM
 Table 5. Compatibility and Stability Concerns Throughout the PN Process
Process Considerations for compatibility and stability

PN access • Route: central vs. peripheral

• Other IV products to be administered such as:
− Pressors, antibiotics, chemotherapy, blood products, biologics
• Short- or long- term duration
• PN base formula
• Osmolarity (limit to <900 mOsm/L if peripheral)
• Will ILE and/or electrolytes be administered separately from PN?

PN prescribing/order • PN base formula: dextrose/AA with ILE separate, TNA

• Individual vs. combination products for multivitamins and trace elements
• Commercially available dextrose/AA or TNA stored in separate sections of final
container
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l ri Co • PN formula complete and dosed to patient clinical need
gh
ts pyrig
• Do any nutrients require supplementation outside of PN, such as ILE, electrolytes,
vitamins, fluids?
re
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PN compounding/preparation • Order of mixing
rve 02 • Volume/concentrations of additives
d. 3
Re © compounding device based on best practices and safety guidelines
• Need for implementation of customized alerts and limits on automated

pr M• cUpdate limits and order of mixing each time a different source or manufacturer
od product Ma is used
uc• Identify hoand mitigate processes that facilitate the injection of air/oxygen during
tthe
ionprocess nP
• Sterilein u
wh blistechnique
compounding

o e hin PN is exposed to during transport to the patient unit or

home; packagelto
PN dispensing, storage • Consider the environment
protect g
or fromGUV light and extremes of temperature
in and extremes
r
pa viaoau1.2-micron
PN administration • Protect from light, UV light of temperature
• All PN should be administered p
rt whenuncompatibility
filter
• Coadminister with medications only wi les
t
and stability has been verified
• Consider cyclic infusion of PN if CVC needed hou tosadminister incompatible medication
t oth
AA, amino acid injection product; CVC, central venous catheter; ILE, lipid injectable emulsion;p
er erwnutrition;
PN, parenteral
mi
ss ise
TNA, total nutrient admixture.

ion no
Based on reference 1.

is ted
pr .
oh
Table 6. USP General Chapter <797>: BUDs 2008 Compared With 2022 Version ibi
ted
2008 2022
.
BUD classification for PN Medium risk Category 2 (subcategories: prepared from only sterile starting components
and without sterility testing of the final CSP)

BUD at room temperature 30 hours 4 days

(20° C to 25° C)

BUD under refrigeration 9 days 10 days

(2° C to 8° C)

Important notes A shorter BUD must be assigned when the physical and chemical stability
of the CSP is less than the BUD limit stated in Table 13

BUD, beyond-use date; CSP, compounded sterile preparation.

PHARMACY PRACTICE NEWS SPECIAL EDITION • JUNE 2023 33

interpreting a medication’s compatibility data with PN in Amino Acids
a simplistic manner (e.g., compatible, incompatible, vari- There are numerous formulations of amino acids in
able results or no results/no data available). The user production, and each has unique characteristics that are
may even be greeted with a reassuring symbol such as important to consider for an assessment of compatibility
a check mark when a study exists with favorable com- or stability. Amino acid product compositions vary beyond
patibility results. However, many their crystalline amino acid makeup
results may summarize findings in many ways, including electro-
from older studies that used PN Compatibility data for one ILE lyte content (sodium, phosphate,
formulations not reflective of cur- formulation (either separate from chloride, acetate), osmolarity and
rent PN practice and/or PN ingre- pH. These differences can signifi-
dients that may no longer be
PN or within a TNA) cannot be cantly affect the safety of a PN for-
available. Details beyond “com- extrapolated to other ILE products. mula. For example, higher doses
patible” or “incompatible” must be or concentrations of amino acids
evaluated because a difference will result in a lower final pH of the
in just one ingredient may substantially change the char- PN admixture and, thus, increase the solubility of calcium
acteristics of the final PN admixture. The PN formulation and phosphate. Depending on the product, the pH of the
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being compounded must be compared with the PN for- amino acid ingredient could range from 5 to 7, so even at
l ri Co
gh
mulations and products used in the studies, and judged the same dose/concentration, a substitution of the amino

ts pyrig
whether they are comparable to make the compatibility acid formulation may substantially change the final pH of the
re PN admixture.3
se ht 2
and stability decision. If this is not known, the manufac-
turer of the PN products on formulary must be contacted
rve 02
for their product-specific compatibility and stability stud- Filters
d. 3
ies, as these data often exist, but must be requested. This Many variables can affect compatibility and stability
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is also a critical concern for PN product shortages and of the PN admixture, which could lead to particulate for-
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use of non-formulary products or products imported from mation or destabilization of ILE. Most particulates are

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other countries. Although certainly not a complete list, not visible to the naked eye, and if inadvertently infused,
major considerations of specific
tio on can result in significant patient
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PN components are described harm or death. The risk for expo-
in the next two paragraphs, and Pharmacies and clinicians should sure to particulates is increased
an example of a medication’s
ho lish
continue to apply a 30-hour BUD for even more when medications
compatibility data with PN is le ing are co-infused with PN. Even if
or
PN formulations stored at controlled
in Gro
provided for practical applica- medications are listed as being
tion in Figure 1. room temperature, even after the 2022 compatible with PN, it is impos-
pa up sible to replicate every possi-
rt
wi unle
Lipid Injectable Emulsion USP Chapter <797> standards have
ble custom PN formulation and
tho ss
There are at least five dif- been implemented at their institutions. the exact environmental scenar-
ferent brands of ILE on the ut o ios that could occur during co-
U.S. market, and all but two of pe the infusion. Filters are the last line
them are formulated with one or more fat source in ratios rm rw
of defense against infusion of particulate matter from an
that are unique to each product. Most compatibility data iss ise
unstable or chemically incompatible PN formulation. A sin-
for total nutrient admixtures (TNAs) in tertiary resources ion no
gle 1.2-micron filter must be utilized for infusion of PN solu-
include brands of ILE containing 100% soybean oil (SO-ILE), is ted
tions in all settings, as recommended by the American
with fewer studies available for mixed oil or 100% fish oil pr .
Society for Parenteral and Enteral Nutrition.9
oh
ibi
ILEs. Compatibility data for one ILE formulation (either sep-
The Rationale for Not Extending BUDs Beyond
arate from PN or within a TNA) cannot be extrapolated to
4
other ILE products. If a clinician is questioning the com- 30 Hours te d.
patibility of a medication with a PN formula containing an Pharmacies and clinicians should continue to apply a
ILE product that is not represented in their search results, 30-hour BUD for PN formulations stored at CRT, even after
such data should be requested from the manufacturer. the 2022 USP Chapter <797> standards have been imple-
Likewise, the stability data for one ILE formulation in a TNA mented at their institutions. The rationale is summarized in
cannot be extrapolated to other ILE products.3,4 Although the box (page 36). Maintaining BUDs for 30 hours at CRT
many clinicians may target final concentrations of amino is fundamental to preventing the administration of unsta-
acids ≥4%, dextrose ≥10% and ILEs ≥2% for all TNAs, these ble PN formulations. Extending the BUD from the original
percentages only represent the optimal stability for TNAs 2008 USP Chapter <797> guidance of 30 hours to four days
containing SO-ILE.8 For all other ILE formulations, clinicians at CRT can have significant consequences on both chem-
should request from the manufacturer the concentration ical and physical characteristics of these highly complex
ranges shown to be stable in a TNA for the specific prod- admixtures. It has been clearly documented that the Mail-
uct in question. lard reaction occurs during combination of IV dextrose with

34 PHARMACYPRACTICENEWS.COM
 Patient Case Table 2. Details of Compatibility Study
A nurse calls the inpatient pharmacy to ask whether it is safe
Study 1 Note
to co-infuse an IV antibiotic with a patient’s parenteral nutrition
(PN). The patient’s central venous access only has one lumen, Simulated y-site study The TNA had
and nursing staff has been unable to obtain peripheral IV using glass containers and the following
access for infusion of their antibiotic. In searching the literature study duration of 4 hours; composition per liter:
for compatibility, the pharmacist helping the nurse finds in a medication solution and amino acids 56 g
tertiary reference that the antibiotic has been tested for y-site PN admixture (PN brand dextrose 144 g,

Details in hyperlinks
compatibility with a total nutrient admixture (TNA), and the 3-chamber PN bag) were lipids 40 g,
result is “compatible.” (Details are below in Table 1; “Study 1” combined sodium 54 mEq,
and “Note” in blue text represent hyperlinks visible to the RESULTS potassium 38 mEq,
pharmacist in their search results.) The patient’s actual PN Physical compatibility: calcium 8.4 mEq,
formula contains 110 g of amino acids 15% (Clinisol, Baxter), 215 • Physically compatible; magnesium 8.4 mEq,
g of dextrose, 30 g of lipid injectable emulsion (ILE) composed no haze, discoloration phosphate 16 mmol,
of soybean oil (SO), medium-chain triglycerides (MCTs), olive or precipitation seen on chloride 48 mEq,
Al oil (OO) and fish oil (FO), 30 mEq of sodium acetate, 30 mmol visual observation; visual acetate 48 mEq
l ri Co
of sodium phosphate, 40 mEq of potassium chloride, 10 mEq
gh
inspection performed with

ts pyrig
of calcium gluconate, 8 mEq of magnesium sulfate, 10 mL and without lipids to aid in
of a multivitamin (adult, with vitamin K) and trace elements
re
se ht 2
visual observation
injection-4 1 mL (Tralement, American Regent) in a total volume
Chemical stability:
of 1,320 mL.
rve 02 • No information available
d. 3
©
Reof Compatibility
pr Mc
Table 1. Initial Results Search
od M Question 2. Is there now enough information to make a
uc ah
Compatibility Study 1 recommendation about co-infusion of the antibiotic with the
tio on
study patient’s PN? If so, what is the recommendation and why?
Antibiotic (50 mg/mL) inn sodium
in Pub Answer: Yes, now all information contained within the
Drug chloride 0.9%
wh lis compatibility search result has been evaluated. This
Solution ole hinthe actual and study PN formulas as well as several other
TNA (3-in-1) Total Nutrient Admixture
additional information reveals many differences between

g Gdetails that should lead the clinician to recommend

or study
Finding Compatible
inagainstroco-infusion of the antibiotic with the PN. These are
pa upin Table 3. Of note, if the PN admixtures were
morertcomparable,
Note Note summarized
un identification of the ILE formulation used
wi should
in the studyt h lebe
sstheformulation
next step. If the PN formulas were
similar and theostudy ILE
Question 1. Based on the information provided above, ut actual othPN, then itwas identical to that
should the pharmacist tell the nurse that it is safe to
used in the patient’s p er of etherwantibiotic at a y-site above
would be reasonable
to recommend co-infusion
mi
ss ise
co-infuse the antibiotic with the patient’s PN?
the 1.2-micron filter.
Answer: No, the table above does not present enough
ion no
is ted
information to determine whether the antibiotic is safe for

Environment Versus Actual PN pro .

co-infusion with this patient’s PN. The pharmacist should Table 3. Differences in Study PN/Study

hib
review the detailed information about the study and notes
about the PN formula and compare this with the patient’s
PN admixture ite
dand
actual PN formula and antibiotic.
The pharmacist reviews the antibiotic order and finds that • Study PN has lower concentrations of amino acids
dextrose and would have an overall lower osmolarity
.
it is diluted in sodium chloride 0.9% to a concentration
identical to that in the study. The patient’s actual PN formula than the actual PN
is also reviewed and contains 110 g of amino acids 15%, • Study PN formula has no IV vitamins or trace elements
215 g of dextrose, 30 g of ILE composed of SO, MCTs, • ILE formulation of study PN is unknown
OO, FO, 30 mEq of sodium acetate, 30 mmol of sodium Study methods
phosphate, 40 mEq of potassium chloride, 10 mEq of
calcium gluconate, 8 mEq of magnesium sulfate, 10 mL of • Study PN and antibiotic are stored in glass containers
a multivitamin (adult, with vitamin K) and trace elements • Only physical compatibility is tested, not chemical
injection-4 1 mL in a total volume of 1,320 mL. After opening stability
the links in the compatibility summary table, the information • Physical compatibility is only tested by visual inspection
in Table 2 is revealed. (most particulates are sub-visible)

PHARMACY PRACTICE NEWS SPECIAL EDITION • JUNE 2023 35

amino acids for preparation of PN (Table 2).10 In this reaction, Depending on the relative concentrations of calcium and
a reducing sugar (e.g., glucose) and an amine (e.g., amino phosphate salts, the formation of precipitates may take up
acid) react to form aldosylamines, which ultimately produce to 24 to 48 hours at 37° C. Once precipitates form, they are
amber-yellow-brown Maillard reaction products. highly unlikely to redisperse.14 As mentioned previously,
Although little data exist about toxicity associated with most precipitates are sub-visible.
parenteral infusion of Maillard reaction products, infants Numerous physical and chemical concerns exist when
receiving PN formulations containing these complexes have BUDs are extended for PN formulations compounded with
been noted to become dehydrated more ILEs. ILEs are slightly alkaline and do
readily.11 An association of these com- not contain preservatives. Both of these
plexes with excessive urinary excretion Time and temperature characteristics support the growth of
of zinc, copper and iron in both infants gram-positive and gram-negative bac-
and adults has also been noted, appar- are the enemies teria and fungi if inadvertently contam-
ently reflecting trace metal chelation and of PN stability. inated. Fungal strains grow more slowly,
failure of reabsorption from the glomeru- but still reach concentrations compara-
lar filtrate.11-13 ble to those of bacteria within 24 hours.15
Stability of PN formulations is imperative for patient The potential for in-use contamination of ILEs has led the
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safety. One of the most lethal consequences that can result CDC to limit the hang-time for ILEs to 12 hours when they
l ri
Co
gh
from the assignment of excessively long BUD for PN admix- are administered separately from PN, with tubing changes

ts pyrig
tures is the formation of rigid, crystalline precipitates. The every 24 hours.16 However, when ILE is given as a compo-
re
se ht 2
most notorious involves respiratory arrest and death from nent of PN in a TNA, the risk for infections is lower due to a
the precipitation of the insoluble product, dibasic calcium lower pH and higher osmolality of the final admixture. Such
rve 02
phosphate (CaHPO4), in PN formulations with subsequent admixtures and the accompanying administration set should
d. 3
infusion into patients.14 Many factors, such as pH, final con- not be used beyond 24 hours of infusion. No data exist as
Re ©
centration of amino acids and dextrose, compounding to the proliferation of microbial growth within TNAs when
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sequence, calcium salts, and time of storage at CRT before administration or storage time exceeds 30 hours at CRT.

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administration may affect the solubility of CaHPO4 (Table 2). USP considers the infusion of large-diameter fat glob-
tio on ules in ILEs a significant clinical risk and potential health
ni
n w Pub
hazard to patients receiving PN. This is exemplified by the
following statement that appears in USP Chapter <729>,
ho lish Globule Size Distribution in Lipid Injectable Emulsions ref-
le ing erence standards: “The size of the lipid droplets is critical:
or
in Gro
because of mechanical filtration, larger-size fat globules (>5
µm) can be trapped in the lungs.”17 The reticuloendothe-
pa up lial system (RES) is an important component of the immune
rt
wi unle defense system and participates in the clearance of triglyc-
tho ss erides from the human body.18 The RES is represented as
ut o fixed macrophages lining the sinusoids and microvascula-
pe the ture of vital organs such as the lungs, liver, spleen and bone
rm rw marrow, and might be adversely affected by the infusion of
iss ise
ILEs with an excessively high concentration of large-diam-
ion no
eter fat globules.19 Infusing unstable ILEs in experimental
is ted
animal models has produced organ damage. In one case,
Recommendations and Rationale for PN Stability
pr .
a severely unstable lipid emulsion caused hepatic dam-
Maintain PN BUD at 30 oh
ibi
age within 24 hours, whereas in a different case, a modestly

hours for controlled room te

temperature
• Individual PN components are susceptible to instability
after 30 hours at controlled room temperature
(e.g., dextrose, ILEs, calcium/phosphorus).
• PN stability and compatibility are essential for patient
safety—not just sterility.
• Extended shelf-lives (expiration dates) of commercially
available MCBs do not apply to pharmacy-prepared
custom MCBs.
BUD, beyond-use date; ILEs, lipid injectable emulsions;
MCBs, multi-chamber bags; PN, parenteral nutrition.
unstable lipid emulsion produced the same adverse effect
d.
within three days, suggesting a cumulative toxic effect.20,21
Previous human data also suggest that the liver is the princi-
pal organ injured by the infusion of unstable ILEs.22,23 Thus,
the stability of lipid emulsions in TNAs changes over time,
and prolonged exposure of PN formulations at CRT is a less
stable condition than refrigeration. Considering all of these
observations, it emphasizes an important point: Time and
temperature are the enemies of PN stability.
The impact of exceeding BUDs for PN admixtures has
implications both for the inpatient setting as well as the
home care environment. PN formulations compounded for
the inpatient setting should not be exposed to CRT for lon-
ger than 30 hours after preparation, which accounts for six
hours of compounding time and 24 hours of infusion time.

36 PHARMACYPRACTICENEWS.COM
 Otherwise, PN formulations should be stored under refrig-
eration (2° C to 8° C) as soon as possible and must be used
within 10 days after preparation (as a Category 2 CSP). The
BUD limit of 10-day storage conditions (2° C to 8° C) for PN
becomes more important for the home care setting, as
it accounts for transport of (one to two days) of a week’s
PN supply (seven days), followed by one day at CRT during
infusion. This extended BUD allows home infusion providers
to only have to ship once (vs. twice per week) to patients
and is less costly for providers while improving the quality of
life for patients.
To further extend stability of PN formulations, some inpa-
tient and home infusion pharmacies have attempted to uti-
lize multi-chamber bags (MCBs) for compounding custom
PN formulations. In this scenario, a custom PN formula is
compounded per usual processes, but the final admixture is
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pumped into an empty MCB, with one chamber containing
l ri Co
gh
ILE and the other containing all other ingredients, exclud-
ts pyrig
ing manual additives. The custom MCB requires activa-
re
se ht 2
tion and mixing just prior to administration, as is the case
with commercial MCB PN products. Although standardized
rve 02
commercially available MCB PNs are manufactured for the
d. 3
U.S. market and have a shelf-life of up to two years prior
Re ©
to activation, these products are technologically different
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from custom MCB PN that are extemporaneously prepared
uc ah
tio on
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References
ho lish
1. USP General Chapter <797> Pharmaceutical Compounding—Ster-
ile Preparations. USP; 2022.
le in14.
or g Grevisited again. Am J Health Syst Pharm 2008;65(1):73-80.
2. FDA. Safety alert: hazards of precipitation associated with paren-
teral nutrition. Am J Hosp Pharm. 1994;51(11):1427-1428.
in 15. KimroCH, Lewis DE, Kumar A. Bacterial and fungal growth in intrave-
3. Boullata JI, Mirtallo JM, Sacks GS, et al. Parenteral nutrition com-
patibility and stability: a comprehensive review. JPEN J Parenter
Enter Nutr. 2022;46(2):273-299.
4. Mirtallo JM, Ayers P, Boullata J, et al. ASPEN lipid injectable emul-
sion safety recommendations, part 1: background and adult
considerations. Nutr Clin Pract. 2020;35(5):769-782.
5. USP General Chapter <797> Pharmaceutical Compounding—Ster-
ile Preparations. USP; 2008.
6. Kastango ES. Blueprint for implementing USP chapter 797 for
compounding sterile preparations. Am J Health Syst Pharm.
2005;62(12):1271-1288.
7. Infuvite [prescribing information]. Baxter Healthcare Corporation;
2016.
8. Boullata JI, Gilbert K, Sacks G, et al. A.S.P.E.N. clinical guidelines:
parenteral nutrition ordering, order review, labeling, and dispens-
ing. JPEN J Parenter Enteral Nutr. 2014;38(3):334-377.
9. Worthington P, Gura KM, Kraft MD, et al. Update on the use of fil-
ters for parenteral nutrition: an ASPEN position paper. Nutr Clin
Pract. 2021;36(1):29-39.
10. Fry LK, Stegink LD. Formation of Maillard reaction products in par-
enteral alimentation solutions. J Nutr. 1982;112(8):1631-1637.
11. Stegink LD, Shepherd JA, Fry LK, et al. Sugar-amino acid com-
plexes in parenteral alimentation. Pediatr Res. 1974;8:396.
12. Stegink LD, Freeman JB, Meyer PD, et al. Excessive trace metal
ion excretion due to sugar amino acid complexes during total par-
enteral nutrition. Federation Proc. 1975;34:931.
PHARMACY PRACTICE NEWS SPECIAL EDITION • JUNE 2023
by pharmacists. During the commercial manufacturing pro-
cess, nitrogen gas is pumped into an empty PN container
to evacuate any oxygen present that may contribute to oxi-
dation and destabilization of ILEs. This specific technique
is responsible for extending the shelf-life of these com-
mercially manufactured PN products. The time point for PN
stability (and sterility) begins once the bag is activated for
administration. It is not feasible to use nitrogen gas to evac-
uate a custom MCB when it is being used for extempora-
neously compounding of PN formulations; thus, the basis
for extended PN stability (and BUD) does not exist. The
disparity between commercial manufacturing and extem-
poraneous compounding results in distinctly different phys-
icochemical conditions that influence admixture stability.
Thus, the advantages realized with commercially manufac-
tured PN products do not necessarily translate to extempo-
raneously prepared PN formulations.
Conclusion
Optimizing PN safety requires attention to not only steril-
ity but also to compatibility and stability of the admixture. Ulti-
mately, it is most prudent for clinicians to maintain the 30-hour
at room temperature BUD from USP <797> 2008 in order to
increase the likelihood of the PN formulation maintaining sta-
bility throughout the entire PN administration period.
13. Freeman JB, Stegink LD, Meyer PD, et al. Excessive urinary zinc
losses during parenteral alimentation. J Surg. 1975;18(5):463-469.
Newton DW, Driscoll DF. Calcium and phosphate compatibility:
panous ufatpemulsions. Am J Hosp Pharm. 1983;40(12):2159-2161.
rt Guidelines
wi unlefor the prevention of intravascular cath-
tho infections.
16. CDC.
eter–related ss MMWR Morbid Mortal Wkly Rep.
u oth
t p Globule
2002;51(RR-10):1-37.
eSize Distribution in Lipid Injectable
er Formulary;
mi rwis2008. USP31/NF26;2008:28.
17. USP Chapter <729>
Emulsions. USP/National
ss e of the reticuloendothe-
ion no
18. Saba TM. Physiology and pathophysiology
s p teparticle
lial system. Arch Intern Med. 1970;126(6):1031-1052.
19. Lutz O, Meraihi Z, Mura JL, et al. Fat iemulsion
d. size: influ-
ro
ence on the clearance rate and tissue lipolytic activity. Am J Clin
hib
Nutr. 1989;50(6):1370-1381.
ite
20. Driscoll DF, Ling P-R, Quist WC, et al. Pathological consequences
from the infusion of unstable lipid admixtures in guinead
Nutr. 2005;24:105-113. .
pigs. Clin
21. Driscoll DF, Ling P-R, Bistrian BR. Pathological consequences to
reticuloendothelial system organs following infusion of unstable
all-in-one mixtures in rats. Clin Nutr. 2006;25(5):842-850.
22. Seidner DL, Mascioli EA, Istfan NW, et al. The effects of long chain
triglyceride emulsions on reticuloendothelial system function in
humans. JPEN J Parenter Enter Nutr. 1989;13(6):614-619.
23. Jensen GL, Mascioli EA, Seidner DL, et al. Parenteral infusion
of long and medium chain triglycerides and reticuloendo-
thelial system function in man. JPEN J Parenter Enter Nutr.
1990;14(5):467-472.
37