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sensitive to various environmental factors such as temperature, pH, light, and agitation. Therefore, optimal conditions must be determined for maintaining the stability
of the biological product over its intended shelf-life. Typically, biological products
are stored at refrigerated temperatures (2–8°C) and protected from light.
The most common route of administration is the parenteral route by injection or
infusion. Indeed, most biologics are injectable products, either consisting of solutions in vials, prelled syringes, and autoinjectors or lyophilized powders/cakes for
reconstitution (Table15.1). Among injectable products, liquid formulations are preferred for enhanced compliance of clinicians and patients since their preparation is
simpler than thawing or reconstituting lyophilized products. When possible, liquid
pre-loaded in syringes and autoinjectors also facilitates self-administration.
Generally, excipients used in biological products are those common to other
injectable pharmaceutical products, including buffering agents (citrate, acetate, histidine, and phosphate), bulking agents (e.g., cryoprotectant and lyoprotectant), and
osmotic and tonicity agents. Importantly, proteins can suffer aggregation or denaturation during processing, which will negatively affect their therapeutic activity.
Therefore, excipients including mannitol, trehalose, sucrose, and histidine and surfactants including polysorbate 20 or polysorbate 80 are used.
The packaging material and container closure system play a critical role in preserving the biological product‘s integrity and preventing contamination. The packaging must be compatible with the product and provide a barrier against external
factors like moisture, light, and oxygen. Most biological products are contained in
vials, ampoules, prelled syringes, and autoinjectors. If the product is formulated
using lyophilization (i.e., freeze-drying), then the nal form of the product in the
vial is in the form of a solid rigid cake (see, Chap. 6, Sect. 6.5), and instructions for
reconstitution are provided by the manufacturer. These instructions specify how the
product should be reconstituted using a specic solvent before administration.
Sterile Water for Injection USP and Bacteriostatic Water for Injection USP are used
to reconstitute lyophilized products, generally with gentle swirling by rotating the
vial without shaking or agitation. Shaking can cause foaming, which can cause
proteins, which can be surface active, to diffuse to and locate at the liquid-air interface. This results in less protein being available for withdrawal from the vial and
possible aggregation and denaturation. Also, some biological products require
Sodium Chloride 0.9% USP as the solvent for reconstitution or dilution.
15 Drug Product Design andDelivery ofBiologics
15.4 Devices forAdministration ofBiological Products
andPerformance Testing
With the exception of products like inhaled insulin (Afrezza®), nebulized dornase
alfa (Pulmozyme®), and cenegermin-bkbj ophthalmic eye drops (Oxerbate®) most
biologics are administered by injection. Injectable formulations require syringes for
administration and, therefore, are commonly contained as a solution in vials, prelled syringes, and autoinjectors (pens) (Fig.15.1).
15.4 Devices forAdministration ofBiological Products andPerformance Testing
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225
Table 15.1
Brand
name
Humira Adalimumab TNF-α
Enbrel Etanercept TNF-α
Rituxan Rituximab CD20
Avastin Bevacizumab VEGF
Herceptin Trastuzumab HER2
Exemplary therapeutic biological products and their formulation composition
Mechanism
of action
and
Active
ingredient
therapeutic
class
inhibitor;
monoclonal
antibody
inhibitor;
fusion
protein
antigen
targeting;
monoclonal
antibody
inhibitor;
monoclonal
antibody
targeting;
monoclonal
antibody
Dosage form,
presentation,
and route of
administration
Solution in
prelled
syringe,
autoinjector, and
vial;
subcutaneous
injection
Solution in
prelled syringe
and autoinjector;
subcutaneous
injection
Lyophilized
powder;
subcutaneous
injection
Solution in vial;
intravenous
infusion
Solution in vial;
intravenous
infusion
Lyophilized
powder for
reconstitution;
intravenous
infusion
Storage
stability
requirements
according to
product label Excipients
Refrigeration
(2–8°C);
protected
from light
Refrigeration
(2–8°C);
protected
from light
Refrigeration
(2–8°C);
protected
from light
Refrigeration
(2–8°C);
protected
from light
Refrigeration
(2–8°C)
Citric acid
monohydrate,
dibasic sodium
phosphate
dihydrate,
mannitol,
monobasic
sodium phosphate
dihydrate,
polysorbate 80,
NaCl, sodium
citrate, and water
Sucrose, NaCl,
L-arginine
hydrochloride,
and sodium
phosphate
Mannitol, sucrose,
and tromethamine
NaCl, sodium
citrate dihydrate,
and polysorbate
80, and water for
injection USP
Trehalose
dihydrate, sodium
phosphate
monobasic,
monohydrate,
sodium phosphate
dibasic anhydrous,
polysorbate 20,
and water for
injection, USP
L-histidine HCl,
L-histidine,
trehalose
dihydrate, and
polysorbate 20
(continued)
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15 Drug Product Design andDelivery ofBiologics
Table 15.1
(continued)
Mechanism
of action
and
Brand
name
Active
ingredient
therapeutic
class
Lantus Insulin glargine Insulin;
peptide
hormone
Neulasta Peglgrastim Pegylated
G-CSF
analog
Lucentis Ranibizumab VEGF-A
inhibitor;
monoclonal
antibody
Eylea Aibercept VEGF-A
inhibitor;
fusion
protein
Keytruda Pembrolizumab PD-1
inhibitor;
monoclonal
antibody
Brineura Cerliponase
alfa
TPP1
enzyme
Dosage form,
presentation,
and route of
administration
Solution in
pre-lled
autoinjector
cartridge and
vial;
subcutaneous
injection
Solution in
pre-lled
syringe;
subcutaneous
injection
Solution in vial;
intravitreal
injection
Solution in vial;
intravitreal
injection
Lyophilized
powder for
reconstitution;
intravenous
infusion
Solution in vial;
intravenous
infusion
Solution in vial;
intraventricular
injection
Storage
stability
requirements
according to
product label Excipients
Refrigeration
(2–8°C);
protected
from light
Zinc, m-cresol,
glycerol,
polysorbate 20,
and water for
injection USP
Refrigeration
(2–8°C);
protected
from light
Acetate,
polysorbate 20,
sodium, sorbitol,
and water for
injection USP
Refrigeration
(2–8°C);
protected
from light
Refrigeration
(2–8°C);
protected
from light
Refrigeration
(2–8°C);
protected
from light
Histidine HCl,
trehalose
dihydrate,
polysorbate 20
Sodium
phosphate, NaCl,
polysorbate 20,
and sucrose
L-histidine,
polysorbate 80,
and sucrose
(140mg)
L-histidine,
polysorbate 80,
sucrose, and water
for injection USP
Freezer
(−25°C to
−15°C);
protected
from light
CaCl
dihydrate,
2
MgCl
2
hexahydrate, KCl,
NaCl, sodium
phosphate dibasic
heptahydrate,
sodium phosphate
monobasic,
monohydrate, and
water for injection
USP
(continued)
15.4 Devices forAdministration ofBiological Products andPerformance Testing
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227
Table 15.1
Brand
name
Oxervate Cenegermin Nerve
Avonex Interferon
TNF-α tumor necrosis factor-alpha, VEGF vascular endothelial growth factor, HER2 human epi-
dermal growth factor receptor 2, G-CSF granulocyte colony-stimulating factor, PD-1 programmed
death receptor-1, TPP1 tripeptidyl peptidase-1, HPMC hydroxypropylmethyl cellulose, PEG polyethylene glycol
(continued)
Active
ingredient
beta-1a
Mechanism
of action
and
therapeutic
class
Growth
factor
Interferon
beta;
immune
modulator
Dosage form,
presentation,
and route of
administration
Solution in vial;
ophthalmic
solution eye
drop
Lyophilized
powder for
reconstitution;
intramuscular
injection
Solution in
prelled
autoinjector;
intramuscular
injection
Storage
stability
requirements
according to
product label Excipients
Freezer
(−20°C)
Refrigeration
(2–8°C);
protected
from light
Disodium
hydrogen
phosphate
anhydrous,
HPMC,
L-methionine,
mannitol, PEG
6000, sodium
dihydrogen
phosphate
dihydrate,
trehalose
dihydrate, and
water for injection
Albumin, NaCl,
dibasic sodium
phosphate,
monobasic
sodium phosphate
Sodium acetate
trihydrate, glacial
acetic acid,
arginine HCl,
polysorbate 20,
and water for
injection
In addition, biological products are administered by injection because of their
low bioavailability when administered by other routes, including oral. Intravenous,
intramuscular, and subcutaneous routes are used in the treatment of cancer, diabetes, and some chronic inammatory diseases. For ophthalmic diseases, the intravitreal route is used to treat macular degeneration by injection, while topical eye drops
are used in the treatment of neurotrophic keratitis. Oxerbate® solution is contained
in a vial, and the product provides a pipette that connects to the vial for product
administration as eye drops. Cerliponase alfa (Brineura®) is delivered into the cerebrospinal uid by intraventricular infusion. The product also provides a catheter and
a reservoir necessary for drug delivery in clinical settings. Finally, the pulmonary
route is used to deliver insulin in a pre-loaded single-use dry powder inhaler
(Afrezza®) and the enzyme dornase alfa by nebulization (Pulmozyme®).
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Fig. 15.1 Example containers and devices used for administration of therapeutic biological products. (a) solution contained in a vial, (b) syringe for administration of solutions, (c) solution contained in a prelled syringe, and (d) solution contained in an autoinjector
15 Drug Product Design andDelivery ofBiologics
The FDA recommends that all glass syringes meet the ISO 11040-4 standard.
Among functional performance tests applicable to syringes and related injectors are
seal integrity testing, glide, break, and separation force, extractables or leachables,
ease of assembly, validation of graduation markings, and dead space. Another recommendation for the injector design is to allow for appropriate visualization of
particulate matter or discoloration of the solution.
15.5 Characterization andPerformance Testing ofBiologics
The Biologics License Application (BLA) is submitted to the FDA to request permission to introduce a biologic product into commerce and requires information on
the applicant, the product and manufacturing, preclinical and clinical studies, and
labeling. BLA must indicate the name, source, and characterization of the production cell line or the procedures used to obtain the transgenic animal or plant. The
purication process must be described to prevent introducing or eliminating pyrogens and viruses.
Biologics include proteins whose biological function depends on their often
complex three-dimensional structure to interact with their therapeutic targets, and
conformational changes can result in loss of activity and therapeutic ineffectiveness.
15.6 Biosimilars
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Different factors can impact protein structure and therefore, biologics tend to be
unstable chemically and physically. The protein’s structure can be modied or
degraded by changes in pH, oxidative or osmotic stress, and ionic strength. In addition, proteins can undergo degradation when exposed to light, temperature, and agitation or shear. The selection of appropriate excipients, such as buffers, surfactants,
cryoprotectants, and lyoprotectants, contribute to maintaining the protein’s physical
and chemical stability during processing and storage.
The determination of the structural integrity of the therapeutic biologic requires
different characterization techniques to show that the protein has not fragmented,
aggregated, or unconjugated during processing and storage. Physical stability can
be measured by the protein’s aggregation when forming larger particles (e.g., high
molecular weight species). Chromatography (HPLC or size exclusion), and mass
spectroscopy can identify protein degradation products and modications like glycation or deamidation. Molecular techniques like Western blot can also be used to
determine physical stability. These techniques are also used in pharmacokinetic
studies.
The specicity of the biologic to its target is studied invitro by immunological
techniques like enzyme-linked immunosorbent assay (ELISA) or ow cytometry,
while potency is tested invivo in an appropriate animal model.
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15.6 Biosimilars
Biological products made from the same types of sources and having the same treatment risks and benets as the biological reference product are referred to as biosimi-
lars. According to the FDA, biosimilars are “highly similar” to the original product
but not identical, due to minor differences that may occur between batches.
Biosimilars are similar to generic small molecule drugs in that they undergo an
abbreviated approval process as compared to an innovator or brand product.
Similar to FDA’s Orange Book of approved small molecule drug products, original biologics, licensed biosimilars, and interchangeable products are registered in
the FDA’s Purple Book: Lists of Licensed Biological Products with Reference
Product Exclusivity and Biosimilarity or Interchangeability Evaluations database.
Interchangeable products are those that can be directly substituted for the reference
product because they count on the support to show the product produces the same
clinical result. For example, according to this database, Humira® (adalimumab) has
one interchangeable product (Cyltezo®) and eight biosimilars. The Purple Book
database also includes licensed vaccines, toxins, products derived from human
blood and plasma, allergens, and gene therapy.
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15 Drug Product Design andDelivery ofBiologics
Futher Reading
Suggested readings for the student include the following texts:
Muralidhara BK, Wong M.Critical considerations in the formulation development of parenteral
biologic drugs. Drug Discov Today. 2020a;25(3):574–81.
Muralidhara BK, Wong M. Critical considerations in the formulation development of paren-
teral biologic drugs. Drug Discov Today. 2020b;25(3):574–81. https://doi.org/10.1016/j.
drudis.2019.12.011.
US Food and Drug Administration (FDA). Purple book database of licensed biological products (6
February 2018). Available at https://www.fda.gov/about- fda/center- biologics- evaluation- and-
research- cber/what- are- biologics- questions- and- answers. Accessed 14 Aug 2023.
US Food and Drug Administration (FDA). What are “Biologics” questions and answers (9 August
2023). Available at https://purplebooksearch.fda.gov/. Accessed 14 Aug 2023.
Williams RO III. Improved formulations to enable stable delivery of biologics. BioPharm Int.
2022;35(7):46–9.
Yi-Heng Percival Zhang and others. Biomanufacturing: history and perspective. J Ind Microbiol
Biotechnol. 2017;44(4–5):773–84. https://doi.org/10.1007/s10295- 016- 1863- 2.
Index
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A
Absolute bioavailability, 17
Absorption, 6, 14, 26, 51, 75, 93, 118, 145,
153, 172, 197, 216, 222
Absorption base, 161
Absorption rate, 17
Abuse (FDA), 88
Adhesion, 56, 163–166, 176, 202, 210
Adhesive layer, 163–165, 176
Aerodynamic diameter, 199, 200, 209, 213
Aggregation, 113–114, 116–117, 121, 122,
125, 127, 139, 147, 199, 224, 229
Air jet milling, 209
Air jet nebulizer, 198, 201–203
Amorphous, 33–36, 40, 66–70, 104
Amorphous solid dispersion (ASD), 33, 34,
44, 67, 70
Antibody-drug conjugates (ADCs), 223
Antioxidants, 42, 80, 98, 102, 105, 138, 192,
208, 217, 218
Anti-tacking agent, 57
Apparent partition coefcient, 30
Area-under-the-curve (AUC), 16, 17, 21
Arrhenius equation, 44–45
Association colloids, 119
Atomization, 34, 201, 202, 204–207, 209, 219
B
Backing layer, 164, 176, 177
BCS Class II, 32
Binder, 54, 55, 57, 59
Bingham/plastic ow, 115
Bioavailability, 7, 15, 17, 18, 20, 26, 28, 29,
33, 67, 69–71, 93, 118, 120, 144,
145, 175, 184, 227
Bioequivalence, 7, 18, 20, 21
Biological products, 21, 209, 222–229
Biologic license application (BLA), 21, 228
Biologics, 19, 21, 197, 222–229
Biopharmaceutics, 14–21
Biopharmaceutics classication system (BCS),
18, 32, 53, 69
Biosimilars, 229
Biotechnology, 222, 223
Brownian motion, 112, 119, 120, 200
Buccal administration, 172, 174
Bulk density, 38, 54
Bulking agent, 57, 59, 105, 224
C
Cake, 105, 113, 114, 224
Cake (lyophilization), 105
Capsule, 19, 43, 49–71, 74, 78, 82, 187,
211, 213
Carrier-based systems (DPIs), 209
Case studies, 2, 3, 8–10
Central compartment, 16, 17
Chelating agents, 98, 102, 144
Chemical stability, 6, 8, 40, 116, 229
Chronotherapy, 86
Circadian rhythm, 86
Coalescence, 134–136, 139, 147
Coarse dispersions, 111, 112
Cocoa Butter, NF, 188, 189, 194
Cold ow, 163, 165
Colloidal dispersion, 111, 118–120, 138–139
Colorant, 51, 57, 59, 62, 127, 177, 178
Comminution, 116
Completely miscible, 95
Compression coating, 84–86
© American Association of Pharmaceutical Scientists 2024
A. D. Brunaugh et al., Essential Pharmaceutics, AAPS Introductions in the
Pharmaceutical Sciences 12, https://doi.org/10.1007/978-3-031-52520-9
231
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Index
Compression molding, 194
Conducting airway, 198, 200
Contact angle, 123, 124
Content uniformity, 61, 64, 220
Controlled release, 6, 54, 59, 67, 77, 80, 82,
162, 186
Co-solvent, 27, 93, 96, 101, 102, 208, 217
Cracking (tablet coating), 56, 63
Cream, 33, 149, 160–162, 167, 186, 187
Critical micelle concentration (CMC), 19, 20,
100, 101, 125, 126, 177, 178
Cryoprotectant, 105, 224, 229
Crystalline, 27, 32–37, 40, 43, 44, 67, 68,
104, 189
Crystalline solid dispersion, 67, 68
Cyclodextrin, 27, 69, 99, 100
D
Dead volume, 202, 203
Deocculated suspension, 113, 114
Delayed release dosage form, 75, 76, 87
Depot injections, 104
Dermis, 103, 153, 154, 156, 159
Device metered (DPIs), 211
Differential scanning calorimetry (DSC),
35–37, 67
Diffusion, 15, 16, 29, 31, 32, 77–79, 81, 120,
154–159, 164, 166, 173, 193, 201
Diffusion (particle deposition), 200
Diffusion cell, 157
Diffusion coefcient, 29, 32, 96, 120, 155,
157, 158
Diluent, 54, 57, 59, 177, 210
Disintegrant, 57, 59, 61, 177
Disintegration, 40, 54, 61–65, 175, 177
Dispersed system, 111, 118, 128
Dissociation constant, 26, 28–29
Dissolution, 6, 26, 28–30, 33, 34, 38, 39, 43,
53, 54, 57, 59, 61, 64, 65, 67, 69,
75, 76, 81–83, 86, 87, 93, 95–96,
117, 118, 120, 146, 173, 175, 185,
190, 193, 200, 207
Distribution, 14–16, 29, 30, 39, 45, 93, 202,
212, 219
Donor and receptor compartments, 32
Dosage form, 2, 14, 25, 49, 74, 93, 122, 142,
153, 172, 182, 216, 225
Dose dumping, 77, 87, 166
Drug, 1, 14, 25, 49, 74, 93, 118, 132, 142, 153,
172, 182, 196, 216, 222
Drug-in-adhesive (DIA), 164, 166
Drug monograph, 29, 61
Drug products, 3, 5–8, 10, 14–21, 25–46, 61,
70, 75, 88, 105, 107, 128, 160, 172,
178–179, 204, 219, 220, 222–229
Dry granulation, 54, 55
Dry gum method, 138
Dry powder inhalers (DPIs), 197, 198,
209–212, 227
Dynamic Vapor Sorption (DVS), 44
E
Edge lift, 163
Electrostatic stabilization, 125
Emulsifying agent (emulsier), 59, 132–138,
140, 188
Emulsion, 34, 59, 111, 125, 132–140, 142,
147, 160–162
Emulsion cracking/breaking, 140
Emulsion creaming, 140
Emulsion settling, 140
Enantiomers, 45, 46
Enemas, 184
Epidermis, 153, 154, 156, 159, 160, 167
Epimerization, 44
Eutectics, 38, 67, 104, 189, 192
Excipients, 10, 26, 27, 29, 33, 34, 38, 39, 43,
49, 52–61, 64, 68, 69, 76, 78, 81,
82, 84, 87, 93, 96–102, 105,
121–127, 134, 138, 140, 149, 153,
165, 167–169, 174, 176–178,
192–193, 207–210, 217, 218, 222,
224, 225, 229
Extended release dosage forms, 54, 75,
77, 78, 87
Extrinsic property, 29
F
Factory metered/pre-metered (DPIs), 211
FDA approved label, 20, 166
Fick’s rst law, 31, 157
Fick’s law, 78, 81, 120, 154–155, 165, 173
Film, 43, 49, 58, 75, 78, 82, 132, 135, 136,
140, 164, 175–178, 211
Film coating, 56–58, 63, 64, 75, 78, 79, 82–84
Film coating polymer, 58, 83
Fine particle fraction (FPF), 213
First order release, 82, 166
Flipped classroom, 1–11
Flocculation, 113–114, 123, 127
Floccule, 113
Food effect, 70–72
Friability, 61, 66
Index
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233
Fusion method (ointment preparation), 162
Fusion proteins, 223, 225, 226
G
Gel, 51–53, 79, 80, 125, 136, 146, 147, 163,
164, 176, 184, 192
Gelatin, 49–51, 137, 163, 178, 190
Generic drug, 18–21
Gibbs free energy, 33, 35
Glass transition temperature, 33, 37,
50, 58, 104
Glidant, 58, 59
Glycerinated gelatin, 188, 190, 194
Granule, 51, 53–55, 69, 84
H
High performance liquid chromatography
(HPLC), 40, 41, 64, 229
High pressure homogenization, 40, 121
Hopper, 52, 54, 69
Hot melt extrusion, 34, 58, 67, 69, 70, 78
Hot-melt method, 165
Hydrocarbon base, 161
Hydrogel, 79, 162
Hydrogenated fatty bases, 189
Hydrolysis, 41, 42
Hydrophile-lipophile balance (HLB) system,
135, 136, 140, 147
Hydrophilic matrix system, 78–81
Hydroxyl value, 189, 190
Hygroscopicity, 38, 43–44, 190, 199
I
Immediate release, 31, 53, 58, 61, 75, 77,
86, 87, 177
Incorporation method (ointment
preparation), 162
Inertial impaction (particle deposition),
199, 200
Information literacy skills, 1, 4, 5, 10
Injectability, 103–104
Injectable administration, 101
Insoluble (hydrophobic) matrix
systems, 81, 82
Intercellular route (passive diffusion), 156
Intramuscular (IM) administration, 102
Intrauterine devices (IUDs), 186, 187
Intravenous (IV) administration, 102
Intravitreal administration, 103
Intravitreal injection, 93, 103, 142, 226
Intrinsic property, 27, 29, 153
Investigational New Drug (IND)
application, 19
Ionization, 6, 26, 28, 30, 31, 94, 115, 185
Iontophoresis, 159
Isotonic, 97, 101, 103
L
Large-volume parenterals, 107
Learning objectives, 5, 6, 9
Lipophilic/hydrophilic, 28–31, 33, 34, 51,
79–82, 100, 119, 122, 123, 125,
127, 135–137, 139, 145, 147–149,
155, 156, 159, 161, 173, 188, 193
Liposomes, 118, 139
Lotion, 160
Lubricant, 58, 59, 192
Lyophilic colloids, 119
Lyophilization, 54, 104, 105, 224
Lyophobic colloids, 119
Lyoprotectant, 105, 224, 229
M
Macrophage phagocytosis, 200
Mass median aerodynamic diameter
(MMAD), 212, 213
Matrix system (vaginal rings), 186
Matrix-type patch, 164
Maximum plasma concentration (C
16, 17, 21
Median diameter, 39
Melting point, 26, 33, 35–38, 67, 104, 161,
163, 188–192, 194
Melt-molding, 194
Membrane controlled systems, 78, 81
Membrane permeability, 28, 31–32
Metered-dose, 176, 178, 213, 219
Micelles, 100, 101, 119, 125, 126
Microbiological stability, 6, 40
Microemulsions, 138
Microneedles, 159, 160
Miscibility, 95, 188
Modied release, 6, 29, 54, 58, 59, 74–88
Monoclonal antibodies (mAbs), 222, 223,
225, 226
Monolithic, 78
Mottling (tablet coating), 56, 62
Mucociliary escalator, 199, 200
Multiparticulates, 78, 82
max
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