e-SPEN, the European e-Journal of Clinical Nutrition and Metabolism 4 (2009) e114–e116

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Clinical Nutrition and Metabolism
journal homepage: http://intl.elsevierhealth.com/journals/espen

Educational Paper

Basics in clinical nutrition: Parenteral nutrition admixtures, how to prepare

parenteral nutrition (PN) admixtures
M.I. Barnett a, Marek Pertkiewicz b, Allan G. Cosslett c, Stefan Mühlebach d
a
Academic Hospital, Maastricht, The Netherlands
b
Medical University of Warsaw, Warsaw, Poland
c
Cardiff University, Cardiff, United Kingdom
d
University of Basle, Aarau, Switzerland

a r t i c l e i n f o

Article history:
Received 13 January 2009
Accepted 27 January 2009

Keyword:
Parenteral nutrition admixtures

1. Learning objectives Historically PN admixtures were prepared at ward level using

To describe the filling methods used for preparation of PN
admixtures
To be familiar with the PN admixture preparation protocol
PN admixtures are sterile large volume parenteral infusions
aseptically manufactured/compounded/prepared from required
nutritional components (e.g. amino acids, glucose, lipid, electro-
lytes, trace elements and vitamins). The individual components
(sterile injections/infusions) are transferred into a single sterile
plastic container, providing the user with a complex pharmaceu-
tical formulation in the form of a single easy to use infusion system.
PN admixtures are usually referred to as Two-in-One (TIO) or All-
in-One (AIO) where these refer to admixtures that are (Fig. 1):
– TIO an aqueous formulation
– AIO infusion which will usually contain all the required PN
components, including lipid in the form of an emulsion
The number of individual components that make up the
admixture may be as many as 50 (Fig. 2), whilst the admixtures may
be required to be stored for periods of up to three months. PN
admixtures are manufactured both industrially and within the
hospital environment. As a result of the complex nature of the
admixtures it is important that an established manufacturing
procedure is established and followed when producing all PN
admixtures.
E-mail address: espenjournals@gmail.com (Editorial Office).
individually packaged sterile components (infusion bottles of
macronutrients; ampoules and vials of micronutrients) by nurses
and clinicians in conditions far from optimal, without the possi-
bility of storing the admixture for future use. As a result microbi-
ological contamination risks were high, although in comparison to
the alternate multiple bottle system there were decreased
complications and the single container system was observed to be
much more convenient to use.
Today, however, to guarantee the stability and microbio-
logical integrity of the PN admixture, strict procedures regarding
the actual practice of manufacture, standards of preparation
environment, and quality control and assurance have been
developed in the majority of PN admixture using countries.
Although pharmaceutical manufacturing conditions may vary in
different PN using countries, PN admixtures should where
possible be manufactured under the best possible aseptic
conditions. These are usually to be found in the pharmacy based
clean room, where the trained personnel have the expertise and
resources for strict aseptic manufacture of parenteral products,
including PN admixtures, under strict validated manufacturing
rules. If the hospital does not have a suitable pharmacy
manufacturing unit within its locality then the purchase of
ready-made PN admixtures from commercial compounding
centres or the use of industrially produced ready-made formu-
lations should be considered. Only if these conditions do not
exist (i.e. in an emergency or during out of hours time periods or
lack of suitable conditions in hospital pharmacy), should ward
based preparation be considered. Even then strict manufacturing
protocols regarding component mixing order and preparation

1751-4991/$ - see front matter Ó 2009 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.eclnm.2009.01.011
 M.I. Barnett et al. / e-SPEN, the European e-Journal of Clinical Nutrition and Metabolism 4 (2009) e114–e116
Bottles with Bottles with All-in-one
Two in one
single combined (3 in 1)
Admixtures
components components admixtures
Amino acids
AIO
Glucose
AIO
Lipid
Ready-to-use (-) (+) + ++
Fig. 1. Two-in-One (TIO) and All-in-One (AIO) systems for parenteral nutrition.
area facilities/conditions should be followed, to protect the
patient.
Some of the reasons why PN admixture manufacture/prepara-
tion should be performed in the hospital pharmacy department
include:
– Well-trained staff, under a PN pharmacist supervision who will
have knowledge of the possible chemical/pharmaceutical
interactions between PN components, thereby helping to solve
potential life-threatening stability problems prior to
manufacture.
– Manufacturing environmental conditions are strictly
controlled and validated, allowing aseptic transference of the
sterile components (e.g. within isolators or laminar flow cabi-
nets), minimizing the risk of microbial contamination.
– The use of validated automated filling devices in larger hospital
pharmacies, allows the production of an increased quantity of
PN admixtures at a decreased cost, so that a greater number of
patients to be fed.
2. Procedures
All of the PN admixture components are usually readily available
as sterile and apyrogenic injections/infusions from pharmaceutical
industrial companies or from hospital manufacturing units. The
aim of the admixing procedure is to aseptically transfer the content
from the individual containers to the final delivery container in
a formulation that provides stability for the necessary period of
storage (if required) and administration to the patient.
Several filling methods are available for use, these include:
– gravity filling of bulk components with small volume products
transferred by syringes
– filling by syringes or volumetric devices (burettes) direct to the
final container.
– filling under nitrogen pressure
– filling under negative pressure (using a vacuum pump)
– using automated admixing devices
3. PN admixture preparation protocols
– The operator must be trained in the rules of admixing; with an
essential knowledge of the rules of aseptic work.
– All admixing surfaces should be cleaned and disinfected, with
routine monitoring of contamination levels performed at all
times.
– Inspection of bottles and ampoules for possible cracks, leaks or
other damages/contaminations should be undertaken. Bottles
and ampoules should be cleaned and disinfected prior to entry
to the manufacturing area.
e115
Components AIO admixture
(> 50)
Limited stability
Dextrose 1.
Na, K, Ca, P Dextrose
Amino acids
Amino acids 2. LCT(MCT) fat
Na, K, Mg Na+
K+
3.
Lipid Ca++
Mg++
4.
Trace elements Phosphate
5. Fe, Zn, Mn, Cu, Cr, Mo, Se, F, J
Vitamins (Vit. A, B, C, D, E, K...)
Fig. 2. All-in-One admixture for parenteral nutrition.
– Components should be assembled in the admixing area in such
a way as to reduce to airflow deviations surrounding the
admixing process (e.g. starting materials to the left of the
operator, there after the operator should continue working in
right hand directions).
– Tear-off closures must be removed, and exposed rubber stop-
pers should be sprayed with a suitable validated disinfectant.
– Electrolyte, trace element and vitamin additions are usually
added by syringe into the separate macronutrient bottles
following strict stability admixing rules, usually issued by
the pharmaceutical industry. Incompatible substances
(e.g. calcium and phosphate) must be added separately. When
manufacturing paediatric or neonatal admixtures, trace
elements and electrolytes may have to be injected directly into
the final container via an injection point due to the reduced
volume of the macronutrients and the greater possibility of
instability occurring.
– Transfer spikes with built in filtered air vents should be inser-
ted into rubber caps and the contents of the bottles should be
transferred by the filling set into final plastic container (this
may be made of Ethylene Vinyl Acetate (EVA) or of multiple
layers of different plastics (multilayered bags). If amino acids
solution containing calcium is transferred first, the bottle,
containing glucose with phosphates must be transferred last.
The bag should be observed during the filling process for signs
of precipitation.
– If an AIO PN admixture is being prepared then the lipid
emulsion must be added last, so that the aqueous phase can be
observed for signs of instability (e.g. precipitation).
– Once all of the components have been added to the final
container then the filling set can be disconnected, the
remaining air pushed out and the filling port closed with clamp
and secured by cap.
– Where chemical stability of vitamins is a problem, then these
should be added via the injection port just prior to use.
– The completed formulation should be labelled, the label to
include the total volume, total component content, the
appropriate administration time and expiration date.
– Depending on the manufacturing conditions and the PN
admixture stability data available then the final container may
be stored at 4  C for the appropriate time period, with an
administration time period usually limited to 24 h.
e116 M.I. Barnett et al. / e-SPEN, the European e-Journal of Clinical Nutrition and Metabolism 4 (2009) e114–e116

Table 1
Different methods of PN admixtures preparation.

Mixing method Product of mixing Additives which should be added in order

to obtain complete PN admixture

Basic preparation By filling separate bag Bag 125–4000 ml Electrolytes, trace elements and vitamins added
– amino acids solutiona to the bottles before or to the bag after mixing
via injection port
– glucose solutiona
– water and/or electrolyte solution
– fat emulsion in separate bottles or containers
Two chamber bag By breaking Bag 1000–2000 ml. Fat emulsion transferred by transfer set after mixing
– containing amino acids and glucose solutions of peelable seals Vitamins and trace elements added after
in two separate chambers without or with fixed mixing by injection
amount of electrolytes When necessary, electrolytes and additional fluids
may be added before adding fat emulsionb
Three chamber bag By breaking Bag 1000–2500 ml Vitamins and trace elements added after mixing
– containing amino acids solution, glucose of peelable seals. via injection port.
solution and fat emulsion in 3 separate Electrolytes and additional fluids may be added
chambers with fixed amount of electrolytes when necessary after mixingb
Industrial mix Already mixed Already mixed Vitamins and trace elements added just before
– containing mixture of amino acids, glucose, use via injection port

fat emulsion
and fixed amount of electrolytes in one ready
to use bag, stored under refrigeration
a
With or without electrolytes.
b
Stability data are necessary and therefore preparation in hospital pharmacy is recommended.

Current pharmaceutical developments in PN admixture tech-
nology, in particular plastic container manufacturer, have seen the
release of standard PN bags either ready mixed or, to provide an
even longer shelf life, with each component in a separate
compartment in the bag. In the latter case the components are
easily mixed just before use by squeezing the bag. These systems
allow standardized formulations to be stored readily available at
room temperature, requiring only vitamins, trace elements and
a giving set to be added to complete the preparation of a complete
AIO admixture (Table 1). In hospitals with no aseptic
manufacturing facilities or in emergency situations these new
systems would seem to provide the answer with regard to
reducing contamination risks in these hospitals. One should
remember however, that even using these more convenient
systems all additives should be added aseptically and according to
written protocol as regarding adding sequence by well-trained
personnel.
Conflict of interest
There is no conflict of interest.
Further reading
1. National Advisory Group on Standards and practice guidelines for parenteral
nutrition. Safe practices for parenteral nutrition formulations. JPEN 1998;22:49.