Excipients' Attributes Crucial for Parenteral Preparations

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The quality attributes of excipients are critical since they impact the quality attributes of
the final formulations. With this in mind, I want to describe the quality attributes
required for parenteral preparations and focus on the main quality attributes required
for each functional excipient used in these types of preparations.

Parenteral preparations are required, like any pharmaceutical dosage forms, to meet the
pharmaceutical quality standards as described in pharmacopeias, and to be safe for the
intended purpose of use (1–4).

First, let us look at the quality attributes for parenteral preparations. These preparations
must be:

Sterile and pyrogen-free

Isotonic (e.g., ensure the tolerability at site of injection)
Close to physiological pH
Clear or practically exempt of visible particles and free of sub-visible particles as
required by pharmacopeias
No evidence of phase separation for the emulsions or aggregates formation for
aqueous dispersion such injectable mAb (monoclonal antibody) preparations
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 Appropriate particle size for suspensions and any sediment readily dispersed upon
shaking to give stable formulations, ensuring the correct dose is administered
Stable through the entire shelf-life (1–4)

Regulatory Views on Excipients

When it comes to excipients, quality attributes are just as critical. Just ask the global
regulators and pharmacopeias.

Excipients may be defined as the constituents of the pharmaceutical form administered

to the patient, other than the active substance (5). In the European Pharmacopoeia, they
are also defined as substances for pharmaceutical use, organic or inorganic substances,
for the production of medicinal products for human or veterinary use.

During pharmaceutical development ICHQ8 (R2) (3), the quality target product profile
(QTPP) is defined and the critical quality attributes (CQAs) of the drug product
(characteristics having an impact on product quality) are identified. Consequently, the
critical quality attributes of the drug substance and excipients are determined by
selecting the type and amount of excipients to deliver a drug product of the desired
quality.

In addition, the ability of excipients to provide their intended function, and to perform
throughout the intended drug product shelf life, should be demonstrated during
pharmaceutical development (3).

The European Pharmacopoeia also developed a general text on the functionality-related

characteristics (FRCs) of excipients (Eur.Ph ; 5.15). The intended function of each
excipient is to guarantee the required physicochemical and biopharmaceutical
properties of the pharmaceutical preparation, and the functionality of each excipient is
determined by its physical and chemical attributes that need to be evaluated only in the
context of a particular formulation and manufacturing process.

The excipient quality attributes related to functionality are called functionality-related

characteristics (FRCs), the monograph section contains FRCs that are known to have an
impact on the functionality of the excipient for the stated uses.

USP has described the functionality of excipient in chapter <1059> Excipient

Performance (1). The key functional categories of the excipients are described along with
the recommended tests or procedures to monitor and control their critical material
attributes (CMAs being a physical, chemical, biological, or microbiological property of a
material). The functional categories are organized by their most typical use and can
apply to multiple dosage forms, including possible association of a functional category
with a particular dosage form.

The Attributes Have It

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The excipients used for parenteral preparations typically fall in the following main
functional categories: vehicles/solvents, tonicity agents, buffers, solubilizing agents (such
solvent and co-solvents, surfactants, complexing agents), bulking agents,
antimicrobials/preservatives, antioxidants, chelating agents and suspending agents (1).

The attributes of these excipients can be separated in two categories: the “universal”
ones applicable to all these excipients and the “specific” ones as per the intended
functionality of each excipient.

Universal Attributes (2,3)

Safe (i.e., biocompatible, viral safety for animal origin)

Endotoxin-free and/or pyrogen-free
Acceptable microbiological quality (e.g., low bioburden)
Sterile if there are no further appropriate sterilization procedures in the
manufacture of sterile dosage forms (or if offered as sterile grade)
Free from residual solvents when applicable
Impurities levels as described in compendia monographs or based on toxicological
data (can be more stringent than those in compendia monographs)
Additional properties (e.g. functionality-related characteristics) defined as the
Critical Material attributes (CMAs) (3)
Able to withstand terminal sterilization or aseptic processing

Table 1 displays each functional excipient with examples of attributes related to their
functionality (1–3).

Table 1 Attributes as Per the Intended Functionality of Each Type of Excipient

FUNCTIONAL
EXCIPIENTS used in EXAMPLE(s) of
parenteral FUNCTIONS ATTRIBUTES

Water for Injection Preferred vehicle/solvent Low organic

(WFI) as it is safe, well tolerated impuritiesas
by the body and easy to measured by total
handle and administer organic carbon
Low inorganic
impurities as
measured by
conductivity
Aluminum content
when intended for
dialysis solutions

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 FUNCTIONAL
EXCIPIENTS used in EXAMPLE(s) of
parenteral FUNCTIONS ATTRIBUTES

Water-miscible Solubilize certain drugs in Macrogels as per FRC in

solvents an aqueous vehicle with Eur.Ph.(1444) when used as
limited amount used due solvents: Viscosity
to toxicity concerns (e.g.,
hemolysis)

Nonwater-miscible Solubilize lipophilic drug Refined olive oil:

solvents substances (most
important group are Acid value: 0,3 max
refined grade oils) Peroxides values: 10
max
Absorbance at 270
nm: 1,2 max

Tonicity agents Make parenteral solutions Solute to be

isotonic with respect to impermeant
blood (to avoid crenation Osmolality measured
or hemolysis) by the method of
depression of freezing
point

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 FUNCTIONAL
EXCIPIENTS used in EXAMPLE(s) of
parenteral FUNCTIONS ATTRIBUTES

Buffer agents Maintain a pH close Buffer capacity in

to physiological one solution, influenced by
Improve drug ratio of salt/acid (or
solubility and base) and total
stability (e.g., to concentration of acid
avoid proteins (or base) and salt
aggregation and Contribution to ionic
precipitation) strength of the
solution (e.g. high
concentration could
result in pain at site of
SC injection)
Physical characteristic,
e.g. particle size that
can impact
manufacturability
(dissolution)

Buffer agents used in As above High collapse

freeze-dried powders temperature to
facilitate a faster
primary drying
Be nonvolatile in
order to prevent pH
drift detrimental to
the product stability
and product loss
during sublimation.
High glass transition
temperature (Tg) to
ensure stability during
storage
Crystallization
behavior (e.g.,
crystallization during
cooling and in frozen
solution could lead to
a decrease in pH)

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 FUNCTIONAL
EXCIPIENTS used in EXAMPLE(s) of
parenteral FUNCTIONS ATTRIBUTES

Surfactants Increase the dissolution Chemical structures

by reducing the surface (e.g., composition of
tension of the drug fatty acid of esters of
substances sorbitan)
Traces of impurities
(e.g., peroxides)
Hydrophilic–lipophilic
balance (HLB)that
influences
performance of the
solubilizers
Critical micelle
concentrations
(CMCs), unique value
for individual
solubilizer with
hydrophilic, lipophilic
and/or hydrophobic
chains.

Complexing agents Increase aqueous Hydroxypropylbetadex, as

solubility and stability of per FRC in Eur.Ph (1804)
drug substances, by when used as solubility-
formation of soluble increasing agent: Degree of
inclusion complex substitution

Bulking agents in Provide an Physical properties:

freeze-dried powders: elegant/adequate freeze-
cryoprotectants dried cake by Physical states of the
and/or lyoprotectants crystallization with non- bulking agent
collapsible structural (amorphous or
integrity (no macroscopic specific crystalline
form)

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 collapse) and that will
FUNCTIONAL
EXCIPIENTS used in reconstitute rapidly
parenteral before FUNCTIONS
administration.
Prevent product loss
caused by blow-out during
freeze drying.
Facilitate efficient drying.
Provide a physically and
chemically stable
formulation matrix.
Lyoprotectants protect
drug substances by
stabilizing and preventing
the degradation through
stable amorphous phase.
Chemical properties:
High critical
temperature,
EXAMPLE(s) above
of
which the freeze-dried
ATTRIBUTES
product loses
macroscopic structure
and collapses during
freeze drying
High eutectic melting
temperature with ice
(allows high primary
drying temperatures
with rapid drying and
subsequent rapid
reconstitution with
diluent)
Glass transition
temperatures (Tg) of
bulking agent impact
the glass transition
temperature (Tg) of
the formulation and
the eutectic melting
temperature of the
crystalline bulking
agent with ice
Low hygroscopicity
(moisture retention
after lyophilization
lead to instable
formulation and poor
reconstitution)
Chemical structure:
e.g., reducing sugars
react with amines of
drug substance
Impurities: e.g., trace
peroxide levels can
initiate oxidative
degradation
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 FUNCTIONAL
EXCIPIENTS used in EXAMPLE(s) of
parenteral FUNCTIONS ATTRIBUTES

Antimicrobial Added to kill (bactericidal Effectiveness of

preservatives or sporicidal) or prevent
microbial proliferation
(bacteriostatic)
antimicrobial
preservative at the
lowest concentration
Assay and acceptable
limits in the drug
product specifications
Vapor pressure (when
used infreeze-dried
formulation)
Partition coefficient
(partitioning into an oil
phase can decrease
preservative's
concentration and
function in the
aqueous phase).
Chemical stability (e.g.,
phenolic preservatives
can undergo oxidation
and color formation)
Compatibility with
drug substances and
other components or
process equipment

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 FUNCTIONAL
EXCIPIENTS used in
parenteral FUNCTIONS
Antioxidants Improve stability by
reducing the rate of
complex oxidative
reaction or delaying the
oxidation of drug
substances and other
excipients
Chelating agents Remove certain metal ions
from solution (Cu, Fe, Mn,
Pb, Ca…) by forming
soluble complex
molecules to minimize or
eliminate their ability to
react with other elements
and/or to precipitate.
Eliminate as well the
capacity of the metal
catalysts to participate in
oxidative reactions
EXAMPLE(s) of
ATTRIBUTES
Effectiveness at the
lowest concentration
Assay and acceptable
limits in the drug
product specifications
Solubility (greater in
the formulation
phase)
Temperature of
decomposition
(impact for terminal
heat sterilization)
Stability at different
pH (oxygen-
scavenging potential
of the reducing agents
may be sensitive to
pH)
Solubility
Affinity for the target
metal ion
Stability, e.g., at
temperature
Compatibility with
other excipients
Particle size if impact
on dissolution rate
during processing
Hygroscopicity
(handling and storage)
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 FUNCTIONAL
EXCIPIENTS used in EXAMPLE(s) of
parenteral FUNCTIONS ATTRIBUTES

Suspending agents Stabilize dispersed Solubility

systems (e.g., suspensions Viscosity
Two main categories : or emulsions) Molecular weight
distribution and
Viscosity
polydispersity of the
increasing
macromolecular
agents
excipients
(hydrophilic
Stability, e.g., at
macromolecules
temperature for
forming gel)
terminal heat
Flocculating
sterilization
agents
Impact on surface
(electrolytes,
charge of the system
surfactant
(zeta potential)
hydrophilic
Particle size if impact
colloids forming
on dissolution rate
loosely bound
during processing
aggregate that
settles rapidly
but re-disperses
easily upon
shaking).

Conclusion
Excipients must meet the pharmaceutical quality standards as described in
pharmacopeias and relevant ICH quality guidelines, and also to ensure the clinical
tolerance as well as to be safe for the intended purpose of use. This is a challenge that I
see, and I hope that the material herein can help parenteral manufacturers identify the
correct quality attributes for their excipients.

Only biocompatible excipients should be used in parenteral preparations. The excipient

attributes, either physical, chemical or biological properties, should be evaluated in the
context of a specific formulation in order to determine the critical material attributes
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(CMAs) and to ensure the critical quality attributes (CQAs) of the final parenteral
preparation.

The views and opinions expressed in this article solely represent those of the authors and do
not necessarily reflect views of the Roquette Group.

References
1. European, US and Japanese Pharmacopeias
2. ICH Q6, Specifications: Test Procedures and Acceptance Criteria for New Drug
Substances and New Drug Products
3. ICH Q8 (R2), Pharmaceutical development
4. Blouet, E. "Parenteral Preparations, Challenges in Formulations." Pharmaceutical
Outsourcing (Nov. 20, 2016).
5. DIRECTIVE 2001/83/EC OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 6
November 2001 on the Community code relating to medicinal products for human
use

About the Author

Dr. Elham Blouet, Pharmacist, has spent several
years in industrial pharma companies having
different positions such pharma development,
quality assurance, regulatory affairs, and
Responsible Pharmacist. She joined Roquette in
2007 with a current position as Global Market
manager for Injectable, Dialysis and Speciality APIs
in the Global Pharma Business Unit.

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