Chapter 1 Injections
And Implanted Drug Products (Parenterals)—Product Quality Tests
Experienced professional in parenteral drug products with expertise in
injections and implanted drug products. Skilled in ensuring quality and safety
standards for both immediate- and extended-release dosage forms. Proficient in
various routes of administration for parenteral drug products. Knowledgeable in
a wide range of parenteral dosage forms, including solutions, suspensions,
emulsions, sterile powders, implants, and drug-device combination products.
Familiar with universal and specific product quality tests for parenteral
dosage forms. Adaptable to regulatory requirements for biologics.
Universal Tests
Identification
Identification tests are discussed in General Notices, 5.40 Identification should
establish the identity of the drug or drugs present in the article and should
discriminate between compounds of closely related structure that are likely to
be present..
Assay
A specific and stability-indicating test should be used
to determine the strength (content) of the drug product. In cases where the use
of a nonspecific assay is justified, other supporting analytical procedures
should be used to achieve overall specificity. A specific procedure should be
used when there is evidence of excipient interference with the nonspecific
assay.
Impurities
Tests for Impurities are discussed
in General Notices, 5.60 Impurities and Foreign Substances.
All articles should be tested to ensure that they meet the requirements.
Foreign And Particulate Matter
Articles intended for parenteral administration should be
prepared in a manner designed to exclude particulate matter as defined in Subvisible Particulate Matter in Therapeutic Protein
Injections 〈787〉, Particulate Matter in Injections 〈788〉,
or Particulate Matter in Ophthalmic Solutions 〈789〉,
as well as excluding other foreign matter as appropriate for the dosage form.
Each final container of all parenteral preparations should be inspected to the
extent possible for the presence of observable foreign and particulate matter
(hereafter termed visible particulates) in its contents. The inspection process
should be designed and qualified to ensure that every lot of all parenteral
preparations is essentially free from visible particulates, as defined in Visible Particulates in Injections 〈790〉.
Qualification of the inspection process should be performed with reference to
particulates in the visible range and those particulates that might emanate
from the manufacturing or filling process. Every container in which the contents
show evidence of visible particulates must be rejected. The inspection for
visible particulates may take place during examination for other defects such
as cracked or defective containers or seals, or when characterizing the
appearance of a lyophilized product.
When the nature of the contents or the container–closure
system permits only limited inspection of the total contents, the 100%
inspection of a lot should be supplemented with the inspection of constituted
(e.g., dried) or withdrawn (e.g., from a dark amber container) contents of a
sample of containers from the lot.
Large-volume injections for single-dose infusion,
small-volume injections, and pharmacy bulk packages (PBPs) are subject to the
light obscuration or microscopic procedures and limits for subvisible
particulate matter set forth in 〈788〉,
unless otherwise specified in the chapter or in the individual monograph. An
article packaged as both a large-volume and a small-volume injection meets the
requirements set forth for small-volume injections where the container is
labeled as containing 100 mL or less. It meets the requirements set forth for
large-volume injections for single-dose infusion where the container is labeled
as containing more than 100 mL.
sterility
The sterility of all drug products intended for
parenteral administration should be confirmed by the use of methods described
in Sterility Tests 〈71〉 or by an
approved alternative method.
bacterial
endotoxins
All articles intended for parenteral administration
should be prepared in a manner designed to limit bacterial endotoxins as
defined in Bacterial Endotoxins Test 〈85〉 or Pyrogen Test 〈151〉.
container
content
Container contents should be determined when appropriate
(see Container Content for Injections 〈697〉).
packaging
systems
The packaging system should not interact physically or
chemically with the preparation to alter its strength, quality, or purity
beyond the official or established requirements. The packaging system should
meet the requirements in ▲Elastomeric Components Used in Injectable
Pharmaceutical Packaging/Delivery Systems 〈381〉▲
(CN 1-Dec-2020), Packaging and Storage Requirements 〈659〉, Containers—Glass 〈660〉, Plastic Packaging Systems and their Materials of
Construction 〈661〉, Plastic Materials of Construction 〈661.1〉, and Plastic Packaging Systems for Pharmaceutical Use 〈661.2〉. Further information regarding packaging systems
testing may be found in Assessment of Extractables Associated with Pharmaceutical
Packaging/Delivery Systems 〈1663〉 and Assessment of Drug Product Leachables Associated with
Pharmaceutical Packaging/Delivery Systems 〈1664〉.
container–closure
integrity
The packaging system should be closed or sealed in such a
manner as to prevent contamination or loss of contents. Validation of container
integrity must demonstrate no penetration of microbial contamination or gain or
loss of any chemical or physical parameter deemed necessary to protect the
product (see Package Integrity Evaluation—Sterile Products 〈1207〉, Package Integrity Testing in the Product Life Cycle—Test
Method Selection and Validation 〈1207.1〉, Package Integrity Leak Test Technologies 〈1207.2〉, and Package Seal Quality Test Technologies 〈1207.3〉).
labeling
All articles intended for parenteral administration should
meet the labeling requirements defined in Labeling 〈7〉.
Specific
Tests
In addition to the Universal Tests listed
above, the following specific tests may be necessary depending on the dosage
form.
uniformity
of dosage units
This test is applicable for parenteral drug products and
dosage forms packaged in single-unit containers. It includes both the mass of
the dosage form and the content of the active substance in the dosage form
(see Uniformity of Dosage Units 〈905〉).
vehicles
and added substances
There are other vehicles, both aqueous and nonaqueous,
beyond those that are discussed below. All vehicles should be suitable for
their intended use and not impact drug product quality.
Aqueous
vehicles:
Aqueous
vehicles must meet the requirements of 〈151〉 or 〈85〉,
whichever is specified in the monograph. Water for injection is generally used
as the vehicle. Sodium chloride or dextrose may be added to render the
resulting solution isotonic, and sodium chloride injection or Ringer's
injection may be used in whole or in part instead of water for injection.
Nonaqueous
vehicles:
Fixed oils
are classified under Nonaqueous vehicles. Fixed oils used as
vehicles are of vegetable origin and are odorless. They meet the requirements
in the test for Solid Paraffin in the Mineral Oil monograph with the cooling
bath maintained at 10°.
Nonaqueous vehicles should also meet the requirements of
the following tests:
·
Fats and Fixed Oils 〈401〉, Saponification Value: Between 185 and 200
·
Fats and Fixed Oils 〈401〉, Iodine Value: Between 79 and 141
·
Fats and Fixed Oils 〈401〉, Unsaponifiable Matter: NMT 1.5%
·
Fats and Fixed Oils 〈401〉, Acid Value: NMT 0.2
·
Fats and Fixed Oils 〈401〉, Peroxide Value: NMT 5.0
·
Water Determination 〈921〉, Method Ic: NMT 0.1%
·
Limit of Copper, Iron, Lead, and Nickel: [Note—The test for nickel is not required if the
oil has not been subjected to hydrogenation, or a nickel catalyst has not been
used in processing.] Proceed as directed in Fats and Fixed Oils 〈401〉, Trace Metals or Elemental Impurities—Procedures 〈233〉.
Meet the requirements in Elemental Impurities—Limits 〈232〉.
Synthetic mono- or diglycerides of fatty acids may be
used provided they are liquid and remain clear when cooled to 10° and have
a Iodine Value of NMT 140.
Added
substances:
Suitable
substances may be added to preparations in order to increase stability or
usefulness unless they are proscribed in the monograph. No coloring agent may
be added to a preparation solely for the purpose of coloring the finished
preparation (see General Notices, 5.20 Added Substances and Antimicrobial Effectiveness Testing 〈51〉).
Observe special care in the choice and use of added
substances in preparations with volumes that exceed 5 mL. The following limits
prevail unless otherwise directed:
·
Mercury and
cationic surface-active agents: NMT 0.01%
·
Chlorobutanol,
cresol, phenol, and similar substances: NMT 0.5%
·
Sulfur
dioxide or an equivalent amount of sulfite, bisulfite, or metabisulfite of
potassium or sodium: NMT 0.2%
antimicrobial
preservatives
Antimicrobial agents must be added to preparations
intended for injection that are packaged in multiple-dose containers unless one
of the following conditions prevails: (1) there are different directions in the
individual monograph; (2) the substance contains a radionuclide with a physical
half-life of less than 24 h; or (3) the active ingredients are themselves
antimicrobial. Substances must meet the requirements of 〈51〉 and Antimicrobial Agents—Content 〈341〉.
water
content
The water content of freeze-dried (lyophilized) products
should be determined when appropriate (see 〈921〉).
aluminum
content
See Labeling 〈7〉, Aluminum in
Large-Volume Injections (LVIs), Small-Volume Injections (SVIs), and Pharmacy
Bulk Packages (PBPs) Used in Parenteral Nutrition (PN) Therapy for
information related to specific labeling requirements associated with aluminum
content.
completeness
and clarity of solutions
The following tests are performed to demonstrate
suitability of constituted solutions prepared before administration. Constitute
the solution as directed in the labeling supplied by the manufacturer:
·
The solid
dissolves completely, leaving no undissolved matter.
·
The
constituted solution is not significantly less clear than an equal volume of
the diluent or of purified water contained in a similar vessel and examined
similarly. Protein solutions may exhibit an inherent opalescence.
The
constituted solution is free from particulate matter that can be observed on
visual inspection (see 〈790〉).
PRODUCT QUALITY TESTS FOR SPECIFIC PARENTERAL DOSAGE FORMS
Product quality tests for the specific dosage forms are
listed below. Specific chapter(s) referenced for the test can be found in
the Universal Tests and Specific Tests sections.
Solutions
A solution is a clear, homogeneous liquid dosage form
that contains one or more chemical substances (e.g., drug substances or
excipients) dissolved in a solvent (aqueous or nonaqueous) or a mixture of
mutually miscible solvents. Solutions intended for parenteral administration
(e.g., by injection or for irrigation) must be sterile and biocompatible with
the intended administration site. This includes consideration of factors such
as tonicity, pH, pyrogenicity, extraneous particulate matter, and
physicochemical compatibility, among others.
Unless otherwise justified, the following tests are
required for solutions for injection:
·
Universal Tests
·
Specific Tests
o
Antimicrobial Preservatives
Sterile
Powders for Solutions
Sterile powders for solutions (also referred to as
sterile powders for injection) consist of drug substances and other components
as dry-formulation ingredients to ensure the chemical and physical stability of
the presentation within a final-use container. Companion sterile diluent or
diluent compartments may be provided to facilitate constitution to the desired
final volume.
The sterile article for injection may be presented in
several forms: lyophilized powder intended for final solution, powdered solids intended
for final solution, or dry solids that form viscous liquids upon constitution.
The description should include a section that deals with
ease of dispersion and reconstitution. The dosage form is a homogeneous solid
that is readily constituted to the final form with the specified diluent, and
dispersion is completed with gentle agitation.
Unless otherwise justified, the following tests apply to
sterile powders for injection:
·
Universal Tests
The following applies to constituted solutions:
·
Chapter 〈905〉:
To ensure the consistency of dosage units, each unit in a batch should have a
drug substance content within a narrow range around the label claim. Dosage
units are defined as dosage forms that contain a single dose or a part of a
dose of drug substance in each unit. For liquid dosage forms analysts should
conduct the assay on an amount of well-mixed constituted material that is
removed from an individual container under conditions of normal use, should
express the results as delivered dose, and should calculate the acceptance
value.
The following applies to dry cake:
·
Loss on Drying 〈731〉: The procedure set
forth in this chapter determines the amount of volatile matter of any kind that
is driven off under the conditions specified.
·
Chapter 〈921〉:
Water or solvent content may have important effects on reconstitution and
stability. For articles that require water or solvent content control, analysts
should perform one of the methods described in 〈921〉 or
a suitable replacement.
·
Appearance: Analysts
should assess the level of and the unit variation for the following parameters:
o
Color of
Dry Cake: Varies within target parameters
o
Texture and
Homogeneity of Dry Cake: Varies within target parameters
o
Presence of
Foreign Material: All units with visible foreign material must be rejected
Suspensions
Parenteral suspensions are liquid dosage forms that
contain solid particles in a state of uniform dispersion. Suspensions for
parenteral administration must be sterile and compatible with the
administration site. Consideration should be given to pH and pyrogenicity, and
appropriate limits should be identified. Physical stability evaluations of
parenteral suspension preparations should include evaluations to confirm that
the particle size range of suspended matter does not change with time and to
confirm that the solids in the preparation can be readily resuspended to yield
a uniform preparation.
The following tests are required for suspensions for
injection unless otherwise justified:
·
Universal Tests
·
Specific Tests
o
Uniformity of Dosage Units
o
Antimicrobial Preservatives
Liposomes
Liposomes are unique drug products with unique properties
that can be either solutions or suspensions. Liposomes are aqueous dispersions
of amphiphilic lipids and have low water solubility. They are organized as a
bilayer sheet that encloses an internal aqueous compartment and are known as
lipid bilayer vesicles. Liposomes can have a single lipid bilayer (unilamellar
vesicle) or can have an onion-like multilayered structure (multilamellar
vesicle). The amphiphilic lipids comprise a hydrated head group at the water
interface of the bilayer attached to a hydrophobic group that forms the
interior of the bilayer by association with the hydrophobic group of lipids
from the opposite leaflet of the bilayer. The physical properties of the
liposome and its bilayer can vary widely and depend on lipid composition,
aqueous composition, and temperature relative to the acyl components' phase
transition points. Because of the central aqueous compartment, a simple test
for the presence of liposomes in a lipid dispersion is to determine the
presence of an entrapped aqueous phase.
A liposome drug product consists of the drug substance,
liposome components, and other inactive but critical ingredients such as an
aqueous dispersion unless the contents are a lyophilized product.
Unless otherwise justified, the following tests are
required for liposomes:
·
Universal Tests
·
Specific Tests
o
Globule Size Distribution in Lipid Injectable
Emulsions 〈729〉
Sterile
Powders for Suspensions
Sterile powders for suspensions consist of drug
substances and other components as dry-formulation ingredients to ensure the
chemical and physical stability of the presentation within a final-use
container. Companion sterile diluent or diluent compartments may be provided to
facilitate constitution to the desired final volume.
The sterile article for injection may be presented in
several forms: lyophilized powder intended for final suspension, powdered
solids intended for final suspension, and microparticles that retain their
integrity and are delivered as a sterile suspension. The description should
include a section that deals with ease of dispersion and reconstitution. The
dosage form is a homogeneous solid that is readily constituted to the final
form with the specified diluent, and dispersion is completed with gentle
agitation.
Unless otherwise justified, the following tests apply to
sterile powders for injection:
·
Universal Tests
Microparticles:
Some
microparticles are provided as a sterile powder to be reconstituted as a
suspension before injection. The majority of microparticle preparations are for
reconstitution as a suspension for injection. For quality test requirements,
please refer to Implants.
Emulsions
Emulsions for parenteral dosage forms are liquid
preparations of drug substances dissolved or dispersed in a suitable emulsion
medium. Oil-in-water or water-in-oil emulsions typically entrap the drug
substance.
Emulsions typically are white, turbid, homogeneous liquid
dosage forms that contain one or more chemical substances (e.g., drug
substances and excipients) dissolved in a solvent (aqueous or nonaqueous) or
mixture of mutually miscible solvents. Emulsions intended for intravenous
administration must be sterile and must be compatible with the intended
administration site.
Unless otherwise justified, the following tests are
required for emulsions for injection:
·
Universal Tests
·
Specific Tests
o
Chapter 〈729〉
Implants
Implants for extended release consist of a matrix of drug
substance and polymeric excipient that may or may not have an outer
rate-controlling membrane. The polymeric excipient must be biocompatible but
may or may not be bioresorbable. Some implants are made from medical-grade
metal with an osmotic pump inside that effects the extended release of the drug
substance. Implants must be sterile and usually are formed in the shape of a
cylinder, although other shapes are used. Solvents used to dissolve the formulation
can lead to sterilization, and thus the internal sterility test method should
demonstrate that the sample preparation does not lead to sterilization of the
test sample.
Cylindrically shaped implants for systemic delivery
usually are provided in an inserter for subcutaneous or local administration
such as local ocular delivery. Implants also can be surgically implanted for
local delivery, e.g., ocular delivery.
Unless otherwise justified, the following tests are
required for implants:
·
Universal Tests
·
Specific Tests
o
Uniformity of Dosage Units
In situ
Gels
Sterile in situ gels are liquid preparations that are
intended for injection into specific therapeutic targets. Typically they
consist of polymers in organic solvents, and upon injection the solvents migrate
away from the site, leaving a gelled mass. The preparations may be injected
as-is, upon reconstitution, from in situ formation, or from chemically
initiated catalysis that results in the final form.
Unless otherwise justified, the following tests are
required for in situ gels:
·
Universal Tests
·
Specific Tests
o
Antimicrobial Preservatives
Microparticles
Injectable, resorbable microparticles for extended
release generally range from 20 to 100 µm in diameter. They consist of drug
substances embedded within a biocompatible, bioresorbable polymeric excipient,
e.g., polyester excipients. Microparticles are provided as a sterile powder in
a vial or syringe.
Just before intramuscular or subcutaneous administration,
the microparticle powder should be suspended in an aqueous injection vehicle
(diluent). The injection vehicle usually consists of water for injection,
surfactant, and a viscosity enhancer, and the vehicle may contain a compound
that adjusts osmolality, e.g., a sugar with or without a compound that controls
pH, e.g., an acid. The injection vehicle must be sterile and must be tested
according to requirements for solutions that are intended for parenteral
administration.
Unless otherwise justified, the following tests are
required for microparticles for injection:
·
Universal Tests
·
Specific Tests
o
Uniformity of Dosage Units
o
Water Content
Drug-Eluting
Stents
Drug-eluting stents are tiny metal or polymer scaffolds
used to keep arteries open following a medical intervention; the drug substance
is incorporated into or onto the stent platform. Drug-eluting stents typically
have two components of testing: (1) functional tests that generally are
American Society for Testing and Materials (ASTM) International methods that
fall outside the scope of this chapter and (2) analytical tests.
Unless otherwise justified, the following tests are
required for drug-eluting stents:
·
Universal Tests
·
Specific Tests
o
Uniformity of Dosage Units. The content of the active substance in the dosage
form is applicable for drug-eluting stents packaged in single-unit containers.
The test can be performed by either content uniformity or weight variation
(see 〈905〉).
With appropriate justification, the number of stents needed for this test may
be fewer than the recommended number of stents in 〈905〉.
o
〈88〉Biological ReactivityTests, In Vivo
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