An Expanding Horizon of Complex Injectable Products: Development and Regulatory Considerations

Drug Delivery and Translational Research (2023) 13:433–472
https://doi.org/10.1007/s13346-022-01223-5
REVIEW ARTICLE
An expanding horizon of complex injectable products: development

and regulatory considerations
Kanan Panchal1 · Sumeet Katke1 · Sanat Kumar Dash1 · Ankit Gaur2 · Aishwarya Shinde1 · Nithun Saha3 ·
Neelesh Kumar Mehra4 · Akash Chaurasiya1
Accepted: 3 August 2022 / Published online: 14 August 2022

© Controlled Release Society 2022
Abstract
There has been a constant evolution in the pharmaceutical market concerning the new technologies imbibed in delivering
drug substances for various indications. This is either market-driven or technology-driven to improve the overall therapeutic
efficacy and patients’ quality of life. The pharmaceutical industry has experienced rapid growth in the area of complex inject-
able products because of their effectiveness in the unmet market. These novel parenteral products, viz, the nanoparticles,
liposomes, microspheres, suspensions, and emulsions, have proven their worth as “Safe and Effective” products. However,
the underlying challenges involved in the development, scalability, and characterization of these injectable products are
critical. Moreover, the guidelines available do not provide a clear understanding of these complex products, making it dif-
ficult to anticipate the regulatory requirements. Thus, it becomes imperative to comprehend the criticalities and develop
an understanding of these products. This review discusses various complexities involved in the parenteral products such as
complex drug substances, excipients, dosage forms, drug administration devices like pre-filled syringes and injector pens,
and its different characterization tools and techniques. The review also provides a brief discussion on the regulatory aspects
and associated hurdles with other parenteral products.
Keywords Complex injectables · Liposomes · Multivesicular liposome · Microspheres · Controlled release · USFDA
Abbreviations I.V. Intravenous

AIDS Acquired immunodeficiency syndrome LAR Long-acting release
API Active pharmaceutical ingredient LAIF Long-acting injectable formulation
CNS Central nervous system MVL Multi-vesicular liposome
EMA European Medicines Agency NBCD Non-biological complex drug
GDUFA Generic Drug User Fee Amendments/Act NDA New drug application
I.M. Intramuscular PFS Pre-filled syringe
PSG Product specific guidance
* Akash Chaurasiya rDNA Recombinant DNA
[email protected] RLD Reference Listed Drug
S.C. Subcutaneous
1
Translational Pharmaceutics Research Laboratory, USFDA United States Food and Drug Administration
Department of Pharmacy, Birla Institute of Technology
and Science, Pilani Hyderabad Campus, Medchal District, WFI Water for injection
Jawahar Nagar, Kapra Mandal, Telangana 500078, India
2
Formulation Development, Par Formulations Pvt. Ltd, Navi
Mumbai, Endo India 400 708, India Introduction
3
Research & Development ‑ Injectables, MSN Laboratories
Pvt. Ltd, Pashamaylaram, Sangareddy, Telangana 502307, In the last few decades, the pharmaceutical industry has
India experienced rapid growth in the sterile product market, lead-
4
Pharmaceutical Nanotechnology Research Laboratory, ing to diverse dosage forms. The advances in sterile prod-
Department of Pharmaceutics, National Institute uct formulations like suspensions, emulsions, liposomes,
of Pharmaceutical Education and Research (NIPER), and micro- and nano-particles have reshaped the design
Hyderabad, Telangana 500 037, India
13
Vol.:(0123456789)
434 Drug Delivery and Translational Research (2023) 13:433–472
of therapeutic systems with better safety and efficacy per- nano-formulations. These novel formulations are primarily
spective [1, 2]. Due to the complexity in the design and designed and developed for parenteral applications for better
development of these drug products, they are referred to as therapeutic outcomes, which serve advantages like improved
“Complex Injectable Products” that require extensive studies pharmacokinetic/pharmacodynamic behavior of the drug
and exclusive approval pathways. As per the United States with reduced dosing frequency and minimal adverse effects
Food and Drug Administration Generic Drug User Fee Act [7]. Additionally, sustained-release dosage forms such as
II (USFDA GDUFA II) commitment letter, complex inject- long-acting injectable products facilitate reformulation of
able products comprise of a complex active pharmaceuti- existing conventional pharmaceutical products for improved
cal ingredient (API) (e.g., Copaxone®; Glatiramer acetate clinical application [8]. These complex drug delivery sys-
injection; marketed by Teva Pharmaceuticals USA, Inc.) or a tems also impart in vivo stability to the small and large drug
complex formulation (e.g., Sandostatin L AR® Depot; Octre- molecules, which are prone to degradation in physiologi-
otide acetate for injectable suspension; marketed by Novartis cal conditions [9]. The commercial applications of complex
Pharmaceuticals Corp.). Additionally, it may also consist injectables have been explored widely, ranging from cancer
of complex drug-device combinations where the drug sub- treatment to long-acting depot injection for central nerv-
stance is pre-loaded in the product-specific device (e.g., ous system disorders [10, 11]. The historical turnaround in
EpiPen®; epinephrine pre-filled auto-injector; Marketed by the last few decades dictates the success of drug products
Mylan Specialty LP) (Fig. 1) [3, 4]. These products have belonging to the category of complex injectables, thereby
proven to improve patient compliance and provide effective leading to a soaring interest of pharmaceutical industries
treatment modalities and good market position to pharma- and regulatory agencies in this area (Fig. 2).
ceutical companies with unique intellectual property [1]. Pharmaceutical companies across the globe are gradu-
Developing new drug molecules for mitigating and curing ally shifting their focus towards the development of complex
various diseases is an ongoing and continuous process. Most injectable products that help deliver more therapeutic value
of these new chemical entities developed today have a poor to the patients and provide the opportunity for a sustain-
aqueous solubility and several undesirable physicochemical able market position due to less competition. However, the
properties like short half-life, extensive degradation, high development and approval of these products are challeng-
protein binding, first-pass metabolism, and poor intestinal ing due to complex manufacturing/operation, requirement of
permeability [5]. To overcome such challenges, these mol- highly skilled human resources and subject matter experts,
ecules are being formulated using advanced delivery sys- high capital investment, and time-consuming translational
tems like liposomes, polymer- or lipid-based nanoparticles, activity from the laboratory to the market. Scale-up pro-
microspheres, and nanocrystals [6]. There has been a con- cesses are tedious due to complicated multi-unit operation/
siderable emphasis on the targeted and site-specific delivery manufacturing processes and the usage of uncommon equip-
of therapeutics, which is possible with the development of ment (like high-pressure homogenizer, lipid extruder, and
Fig. 1 Classification of complex injectable products
13
Drug Delivery and Translational Research (2023) 13:433–472 435
Fig. 2 Historic turning points

in the advancement of complex
injectables
the rest). Additionally, the filing pathways for approval of required for the successful characterization of these prod-
complex injectables are also perplexing due to specific qual- ucts. These scientific details will be beneficial to the phar-
ity attributes, non-conventional testing requirements, and a maceutical researchers and industries working in this area.
lack of clarity in regulatory requirements. The ambiguity in
the regulatory filing persists because of the usage of complex
formulation and excipients, complicated characterization of Complex injectable product
the drug products/drug substances/excipients, ill-defined
in vitro drug release assay methods, and scarce models to Complex injectable products are generally categorized based
establish in vivo pharmacokinetics [12]. The common tech- on the complexities associated with the dosage form, spe-
nical challenges, along with their causes and consequences, cialized excipients, drug substances, and drug-device combi-
are summarized in Table 1. nations [13]. Information on various commercially approved
For facile translation of these products from lab to market, complex injectable products is summarized in Table 2.
it becomes imperative to understand the hurdles at various
stages like the development, characterization, scale-up, and Complex active ingredient—complex mixtures
regulatory filing. Considering the clinical and commercial of API, polymeric compounds, and peptides
importance, we have reviewed the possibilities and obsta-
cles associated with the development of complex injectable There has been a constant requirement for novel therapeu-
products. In this review, various types of complex inject- tics to treat chronic conditions with better safety and effi-
able products and their associated problems are addressed in cacy. Hence, this necessity urges the development of APIs.
detail. It also includes various bioanalytical tools/techniques USFDA defines complex active ingredients as peptides,
Table 1 Challenges associated to complex injectables — Cause and Consequence

S. no Causes Consequences
1. Unavailability of comprehensible regulatory guidelines Unclear road map for product development, consecutively
minimizing regulatory approval
2. Discrepancy/deviation in manufacturing, processing, storage and Instability and variability in dosage affecting therapeutic efficacy,
administration and site-specific or systemic toxicity
3. Inappropriate selection and improper quality and grade of Physical and chemical incompatibility and instability leading to
excipients and raw material product degradation
4. Complexity involved in manufacturing process Undesirable characteristics viz, poor entrapment efficiency, particle
size and PDI, etc
5. Thermolabile, radiation-susceptible, larger size particles in Insufficient sterilization
formulation
6. Multi-component complex system Difficulty in characterization thus requiring specific analytical,
in vitro and in vivo tools and equipments
13
Table 2 List of complex injectables approved by USFDA
436
Sr. no Product Drug Drug Dosage Strength Composition Therapeutic ROA Dosage Approval Marketed Ref
name substances substances form indication regimen date by
13
type
Solution
1. Copaxone® Glatiramer Peptide Solution 20 mg/mL, 40 mg/ Mannitol Relapse from S.C. For Feb 12, 2002 Teva [14]
acetate Pre-filled mL multiple subcutaneous Pharma-
syringe sclerosis injection ceuticals
only. 20 mg/ USA
mL (per day)
40 mg/mL
(thrice per
week)
2. EpiPen® Epinephrine Small Solution 0.3 mg/delivery, Sodium Treatment of I.M., S.C. Patient greater Dec 22, Mylan [15]
molecule Pen device 0.15 mg/delivery chloride, type I than or equal 1987 Specialty
sodium allergic to 30 kg: LP
metabisulfite, reaction EpiPen
WFI including 0.3 mg
anaphylaxis Patient
(15–30 kg):
EpiPen Jr.
0.15 mg
3. Feraheme® Ferumoxytol Iron Solution Equation 30 mg Elemental iron, Iron defi- I.V. (injec- Initial dose Jun 30, 2009 Amag [16]
complex iron/mL mannitol ciency tion) of 510 mg Pharma-
(elemental anemia in followed ceuticals
iron) adult patients by a second
with chronic 510 mg dose
kidney 3 to 8 days
disease later
4. Forteo™ Teriparatide Peptide Solution 0.25 mg/mL Glacial acetic Postmenopausal S.C. Recommended Nov 26, Eli Lilly [17]
Pen device acid, sodium women with dose of 20 2002 and Co
acetate osteoporosis mcg
(anhydrous), subcutaneous
mannitol, meta per day
cresol, WFI
Table 2 (continued)
type
5. Injectafer® Ferric Iron com- Solution 50 mg iron/mL Ferric Iron deficiency I.V. (injec- For patients Jul 25, 2013 American [18]
carboxymaltose plex carboxymaltose anemia tion) weighing Regent
in WFI in adult 50 kg or Inc
patients more: two
doses
separated
by at least
7 days
(750 mg
each dose)
For patients
weighing
less than
50 kg: two
doses
separated
by at least
7 days
(15 mg/kg of
body weight
in each dose)
6. Saxenda® Liraglutide rDNA Solution 6 mg/mL Disodium Chronic S.C. Recommended Dec 23, Novo Nor- [19]
recombinant therapy Pen device phosphate weight dose is 3 mg 2014 disk Inc
dihydrate, management daily. Initiate
propylene in adults at 0.6 mg
glycol, phenol, per day for
WFI one week.
In weekly
intervals, the
dose can be
increased to
3 mg. Dose
for pediatric
patients to be
reduced to
2.4 mg daily
13
437
Table 2 (continued)
438
13
type
7. Somatuline® Lanreotide Synthetic Solution 60 mg/0.2 mL, Acetic acid, WFI Acromegaly, S.C. Recommended Aug 30, Ipsen [20]
Depot acetate cyclical Pre-filled 90 mg/0.3 mL, gastroenter- dosage 2007 Pharma
octapeptide syringe 120 mg/0.5 mL opancreatic Acromegaly: Biotech
neuroendocrine 90 mg every Sas
tumor and 4 weeks for
carcinoid 3 months
tumor GEP-NETs:
treatment 120 mg
every
4 weeks
Carcinoid
syndrome:
120 mg
every
4 weeks
8. Sublocade® Buprenorphine Small Solution 100 mg/0.5 mL, 50:50 PLGA, Opioid S.C. 300 mg as Nov 30, Indivior [21]
molecule Pre-filled 200 mg/mL N-methyl- dependence initial dose 2017 Inc
syringe 2-pyrrolidone treatment (for 2 month)
followed
by 100 mg
maintenance
dose
(monthly)
9. Tymlos® Abaloparatide Hormone Solution 2 mg/mL Sodium acetate Postmenopausal S.C. 80 μg (once)/ Apr 28, 2017 Radius [22]
related Pen device trihydrate, women with day Health
peptide phenol, acetic osteoporosis Inc
acid, WFI
Table 2 (continued)
type
10. Venofer® Ferric Iron complex Solution Equation 20 mg Iron sucrose, Iron deficiency I.V. (Injec- In adult Nov 6, 2006 American [23]
oxyhydroxide iron/mL WFI anemia in tion) patients— Regent
patients hemodialysis- Inc
with chronic dependent
kidney chronic kid-
disease ney disease
(HDD-CKD:
100 mg
Non-dialysis-
dependent
chronic kid-
ney disease
(NDD-CKD):
200 mg
Peritoneal
dialysis
Dependent
chronic
kidney
disease
(PDD-CKD):
300 or
400 mg
In pediatric
patients—
HDD-CKD,
PDD-CKD,
or NDD-
CKD:
0.5 mg/kg
11. Victoza Liraglutide rDNA Solution 6 mg/mL Disodium For S.C. Must be Jan 25, 2010 Novo Nor- [24]
recombinant therapy Pen device phosphate controlling selected disk Inc
dihydrate, glucose according to
propylene level in type desired
glycol, phenol, 2 diabetes dosing
WFI mellitus schedule for
adults
13
439
Table 2 (continued)
440
13
type
Lyophilized powder
12. Advate® Antihemophilic rDNA Lyophilized 250, 500, 1000, Mannitol, Control and I.V. (injec- 20–40 IU per July, 2003 Baxter [25]
factor therapy powder for 1500, 2000, and trehalose, prevention tion) kg every Health-
(recombinant, reconstitu- 3000 IU sodium chloride, of bleeding other day care
plasma/ tion histidine, episode (3–4 times Corp
albumin-free Tris, calcium 37 weekly)
method) chloride,
polysorbate 80,
glutathione
13. Eligard® Leuprolide Peptide Powder for 7.5 mg, 22.5 mg, Leuprolide Prostate S.C. One injec- Jan 23, 2002 Tolmar [26]
acetate reconstitu- 30 mg, 45 mg acetate cancer tion/month Thera-
tion dispersed in containing peutics
PLGH or PLG, 7.5 mg of Inc
NMP API
14. Vfend® Voriconazole Small Powder for 200 mg/vial Sulfobutyl ether Invasive I.V. (infu- Dosage in May 24, Pf Prism [27]
molecule reconstitu- beta-cyclodextrin aspergillosis sion) adults— 2002 Cv
tion sodium, WFI fungal invasive
infection, aspergillosis,
candida candida
infection infections,
scedosporiosis,
and fusariosis:
loading dose
of 6 mg/kg
every 12 h
for first 24 h
followed by
maintenance
dose
Table 2 (continued)
type
Nanosuspension
15. Abraxane® Paclitaxel Small mol- Suspension 100 mg/vial Paclitaxel: albu- Metastatic I.V. (infu- Metastatic Jan 7, 2005 Abraxis [28]
ecule (particle min (1:9) breast sion) breast cancer Biosci-
size: cancer (MBC): ence
130 nm) 260 mg/m2 LLC
Non-small-cell
lung cancer:
100 mg/m2
Pancreatic
adenocar-
cinoma:
125 mg/m2
16. Aristada® Aripiprazole Small mol- Extended 441 mg, 662 mg, Sorbitan Schizophrenia I.M. 441 mg, Oct 5, 2015 Alkermes [29]
lauroxil ecule release 882 mg, monolaurate, 662 mg, Inc

suspension 1064 mg polysorbate 20, or 882 mg
Pre-filled sodium chlo- monthly,
syringe ride, sodium 882 mg
phosphate dose every
dibasic anhy- 6 weeks, or
drous, sodium 1064 mg
phosphate dose every
monobasic, 2 months
WFI
13
441
Table 2 (continued)
442
13
type
17. Invega Paliperidone Small Extended 1092 mg/3.5 mL, Polysorbate 20, Schizophrenia I.M. Gluteal 2006 Janssen [30]
Hafyera® palmitate molecule release 1560 mg/5 mL PEG 4000, in adults injection Pharma-
suspension citric acid once every ceuticals
Pre-filled monohydrate, 6 months. If Inc
syringe sodium dihy- needed, dos-
drogen phos- age adjust-
phate monohy- ment can be
drate, sodium made every
hydroxide, 6 months
WFI between the
dose of 1092
to
1560 mg based
on individual
response and
tolerability
18. Invega Paliperidone Small Extended 39 mg/0.25 mL, Polysorbate 20, Schizophrenia I.M. Schizophrenia Jul 21, 2009 Janssen [31]
Sustena® palmitate molecule release 78 mg/0.5 mL, PEG 4000, and Pharma-
suspension 117 mg/0.75 mL, citric acid schizoaffective ceuticals
Pre-filled 156 mg/mL, monohy- disorder— Inc
syringe 234 mg/1.5 mL drate, sodium initiation
dihydrogen dosing at day
phosphate 1: 234 mg;
monohydrate, day 8:
disodium 156 mg. The
hydrogen recommended
phosphate maintenance
anhydrous, dose is
sodium 117 mg
hydroxide,
WFI
Table 2 (continued)
type
19. Invega Paliperidone Small Extended 273 mg/0.88 mL, Polysorbate 20, Schizophrenia I.M. Once every May 18, Janssen [32]
Trinza® palmitate molecule release 410 mg/1.32 mL, PEG 4000, 3 months 2015 Pharma-
suspension 546 mg/1.75 mL, citric acid after they ceuticals
Pre-filled 819 mg/2.63 mL monohydrate, have been Inc
syringe sodium dihy- treated
drogen phos- with Invega
phate monohy- Sustenna®
drate, sodium for atleast
hydroxide, 4 months
WFI
20. Trelstar® Triptorelin Hormone Suspension Equation 3.75, PLGA, mannitol, Prostate I.M. 3.75 mg every Jun 15, 2000 Verity [33]
pamoate 11.25, 22.5 base/ Na-CMC, poly- cancer 4 weeks; Pharma-
vial sorbate 80 treatment 11.25 mg ceuticals
every Inc
12 weeks;
22.5 mg
every
24 weeks.
Must be
selected
according to
desired
dosing
schedule
21. BydureonB- Exenatide Peptide Extended 2 mg/0.85 mL 50:50 PLGA, Type 2 diabetes S.C. 2 mg once/ Oct 20, 2017 AstraZeneca [34]
Cise ® release sucrose, MCT (diabetes week Ab
suspension mellitus)
Pen device
22. Cabenuva Cabotegravir Small Extended 2 mg/mL Mannitol, Treatment I.M. Initiate the Jan 21, 2021 ViiV [35]
and molecule release cabotegravir polyethylene of HIV-1 injections Health-
Rilpivirine suspension and 3 mg/mL glycol 3350, infection in with 600 mg care
rilpivirine polysorbate 20, adults of cabote-
WFI gravir and
900 mg of
rilpivirine
13
443
Table 2 (continued)
444
13
type
Microspheres
23. Lupaneta® Leuprolide Peptide Microparticle 3.75 mg/vial Purified Painful I.M. Single injection Dec 14, Abbvie [36]
Pack acetate Pre-filled gelatin, symptoms every month 2012 Endo-
dual d-mannitol of for up to six crine Inc
chamber Diluent: endometriosis injections
syringe Na-CMC,
d-mannitol
polysorbate
80, WFI
24. Lupron Leuprolide Peptide Microparticle 7.5 mg, 22.5 mg, Purified Advanced I.M. 7.5 mg for Jan 26, 1989 Abbvie [37]
Depot® acetate Prefilled 30 mg, 45 mg gelatin, prostatic 1-month Endocrine
dual d-mannitol, cancer administration; Inc
chamber PLGA 22.5 mg for
syringe Diluent: 3-month
Na-CMC, administration;
d-mannitol 30 mg for
polysorbate 4-month
80, WFI administration;
45 mg for
6-month
administration.
Must be
selected
according to
desired
dosing
schedule
Table 2 (continued)
type
25. Risperdal Risperidone Small Extended 12.5 mg/vial, Risperidone Schizophrenia, I.M. 25 mg I.M. Oct 29, 2003 Janssen [38]
Costa® molecule release 25 mg/vial, microencapsulated bipolar I every Pharma-
microsphere 37.5 mg/vial, in PLGA disorder 2 weeks. The ceuticals
50 mg/vial Diluent: maximum Inc
polysorbate 20, dose should
Na-CMC, not exceed
disodium 50 mg every
hydrogen 2 weeks
phosphate
dihydrate,
citric acid
anhydrous,
sodium
chloride,
sodium
hydroxide,
WFI
26. Sandostatin Octreotide Peptide Microparticle Equation 10, 20 or Octreotide Acromegaly, I.M. Initial dosing Nov 25, Novartis [39]
LAR® acetate 30 mg base/vial distributed carcinoid is usually 1998 Pharma-
Depot within PLGA tumor 50 mcg ceuticals
copolymer; administered Corp
mannitol twice or 3
Diluent: Na- times daily.
CMC, mannitol, Upward dose
poloxamer 188, titration is
WFI frequently
required
27. Signifor® Pasireotide Peptide Microparticle Equation 10, 20, Pasiriotide Acromegaly, I.M. Initial dosing Dec 15, Recordati [40]
LAR pamoate 30, 40, and pamoate Cushing’s is 40 mg 2014 Rare
60 mg base/vial distributed disease once every Diseases
within PLGA 4 weeks. Inc
copolymer Dose should
Diluent: Na- be adjusted
CMC, mannitol, based on
poloxamer 188, biochemical
WFI response and
tolerability
13
445
Table 2 (continued)
446
13
type
28. Vivitrol® Naltrexone Small Extended 380 mg/vial Naltrexone Alcohol I.M. 380 mg every Apr 13, 2006 Alkermes [41]
molecule release microencapsulated dependency 4 weeks Inc
microsphere in 75:25 PLG through I.M.
Diluent: Na- route
CMC, sodium
chloride,
polysorbate 20,
WFI
Liposome
29. Ambisome® Amphotericin Small Liposome 50 mg/vial Amphotericin Fungal I.V. Empirical Aug 11, Astellas [42]
B molecule (globule B intercalated infection (infusion) therapy: 1997 Pharma
size: to liposomal 3 mg/kg/day US Inc
less than membrane Systemic
100 nm) composed fungal
of HSPC, infections:
cholesterol, 3–5 mg/kg/
DSPG, alpha day
tocopherol and Cryptococcal
sucrose, meningitis in
disodium HIV-infected
succinate patients:
hexahydrate 6 mg/kg/day
buffer
30. Depocyt® Cytarabine Small Multivesicular 10 mg/mL Cytarabine Lymphomatous I.T. Maintenance Apr 1, 1999 Pacira [43]
molecule liposome encapsulated meningitis dose: 50 mg Pharma-
in MVL in every ceuticals
composed of 28 days for 4 Inc
cholesterol, doses (weeks
triolein, 17, 21, 25,
DOPC, and and 29)
DPPG;
suspended in
0.9% w/v
sodium chloride
in WFI
Table 2 (continued)
type
31. Depodur® Morphine Small Multivesicular 10 mg/mL Morphine sulfate Pain Epidural Depending on May 18, Pacira [44]
sulfate molecule liposome encapsulated the criticality 2004 Pharma-
(globule in MVL of the surgery, ceuticals
size: composed of recommended Inc
17–23 μm) cholesterol, dose is
triolein, between 10
tricaprylin, and 20 mg
DOPC, and
DPPG;
suspended in
0.9% w/v
sodium chloride
solution
32. Doxil® Doxorubicin Small Liposome 2 mg/mL Doxorubicin Ovarian I.V. (injection) Ovarian cancer: Nov 17, Baxter [45]
hydrochloride molecule (globule encapsulated cancer, 50 mg/m2 1995 Health-
size: in liposome multiple IV every care
100 nm) composed myeloma 4 weeks Corp
of HSPC, AIDS-related AIDS-related
cholesterol, Kaposi’s Kaposi’s
mPEG-DSPE Sarcoma Sarcoma:
20 mg/m2
IV every
3 weeks
Multiple
Myeloma:
30 mg/m2
IV on day
4 following
bortezomib
13
447
Table 2 (continued)
448
13
type
33. Exparel® Bupivacaine Small Multivesicular 13.3 mg/mL Bupivacaine Inducing I.V. (injection) Oct 28, 2011 Pacira [46]
molecule liposome encapsulated postsurgical Pharma-
(globule in MVL analgesia ceuticals
size: composed of Inc
24–31 μm) cholesterol,
tricaprylin,
DEPC, and
DPPG;
suspended in
0.9% w/v
sodium chloride
solution
34. Onivyde® Irinotecan Small Liposome Equation 4.3 mg Irinotecan Metastatic I.V. (infusion) 70 mg/m2 Oct 22, 2015 Ipsen [47]
hydrochloride molecule (globule base/mL encapsulated in adeno- infusion Biophar-
size: liposome carcinoma over 90 min maceuti-
110 nm) composed of of the in every cals Inc
cholesterol, pancreas 2 weeks
DSPC, mPEG- (combined
2000-DSPE, therapy)
HEPES,
sodium
chloride
Table 2 (continued)
type
35. Marqibo® Vincristine Small Liposome 0.16 mg/mL Vincristine Acute I.V. (injection) At a dose of Aug 9, 2012 Acrotech [48]
sulfate molecule (globule encapsulated lymphoblastic 2.25 mg/ Biop-
size: in liposome leukemia m2 over 1 h harma
100 nm) composed of treatment once in every LLC
sphingomyelin 7 days
and cholesterol
(60:40);
mannitol,
sodium citrate,
citric acid,
sodium
phosphate,
ethanol,
sodium
chloride
Nanoemulsion
36. Cinvanti® Aprepitant Small Emulsion 7.2 mg/mL Egg lecithin, Nausea and I.V. (infusion) 130 mg on day Nov 9, 2017 Heron [49]
molecule dehydrated vomiting 1, infusion Thera-
alcohol, over 30 min peutics
sodium oleate, prior to Inc
soybean oil, chemotherapy
sucrose, WFI (in adults)
37. Cleviprex Clevidipine Small Emulsion 0.5 mg/mL Soybean oil, High blood I.V. (infusion) Initiate I.V. Aug 1, 2008 Chiesi [50]
molecule glycerine, pressure infusion at USA Inc
purified egg 1–2 mg/h.
yolk Further
phospholipids, dose need to
oleic acid, be titrated
disodium based on the
edentate, decrease in
sodium blood
hydroxide pressure.
Maintenance
dose of
4–6 mg/h is
recommended
13
449
polymeric compounds, naturally derived complex mixtures,

or complex mixtures of APIs, including semi-synthetic mix-
[51]
[52]
Ref
tures and other complex substances like iron-carbohydrate
complexes and synthetic nucleotides [53, 54]. Drug sub-
Marketed
Fresenius
peutics
Thera-
TerSera
stances such as the highly potent APIs are also considered
USA
Kabi
LLC
LLC
complex because of their high-risk profile and the require-
by
ment of enhanced containment [55]. Despite their synthetic

Oct 2, 1989
origin, specific drug molecules classified under non-biological

Approval
Dec 29,
complex drugs (e.g., high molecular weight synthetic com-
recommended 1989
date
pounds) attribute intricacies with respect to structure, insuf-

ficient quantification and characterization techniques, and
than 55 years
adults of less
administered
in every 10 s
lack of tools for physicochemical analysis [56]. Recombinant

2.5 mg/kg)
old: 40 mg
onset (2 to
I.V. (infusion) For healthy
induction
28 days
3.6 mg is DNA (rDNA) technology, which involves molecular cloning
regimen
Dosage
every
to be
until
of foreign DNA, produces human proteins in microorgan-

isms. This technology is widely used to produce biophar-
maceutical proteins and gene therapy [57, 58]. However,
the risk of generation of impurities during manufacturing,
discrepancies in gene replication technique, etc., contributes
ROA
Prostate cancer, S.C.
to the complex nature of this product [59].

PLGA copolymer endometriosis
management
For the development and approval of complex API-based

Therapeutic
anesthesia
generic products, it is mandatory to prove pharmaceutical

indication
general
Inducing
cancer,
breast
equivalence (inclusive of the API sameness) of the test

product with a reference product [60]. This is usually estab-
lished by tracking the source of API followed by its thor-
ough characterization, which is a strenuous task. Moreover,
glycerol, egg
Composition
Dispersion of
Soybean oil,
anhydrous
these complex APIs possess unique properties (like structure

acetate in
disodium
goserelin
lecithin,
edetate
matrix
conformities, particle size, and shape) which can only be

characterized by specific and advanced techniques. Thus,
satisfying API sameness and keeping up with the manufac-
turing hurdles amidst usage of advanced characterization
Equation 3.6 mg
tools and techniques builds up the overall intricacy of the

10 mg/mL
product approval.
Strength
of base
Peptides and hormones
Peptides and hormones are generally used for numerous

Emulsion
Implant
Dosage
therapeutic modalities such as the hormonal replacement

form
therapy wherein they add to or supplement if the endog-

enous levels of peptide hormones are inadequate or absent.
substances
molecule
Despite their benefits, the challenge lies in combating its

Hormone
half-life and its successful incorporation into the human

Small
Drug
type
body, as these are naturally occurring substances [61].

Copaxone®, glatiramer acetate injection, is marketed by
Teva Pharmaceuticals Inc. for treatment of multiple sclero-
substances
sis (MS via subcutaneous administration) [14]. Glatiramer

Goserelin
acetate
Propofol
acetate is a mixture of synthetic polypeptides having unique

Drug
anti-inflammatory and immunomodulatory activities [62].

Along with polypeptide-based composition, finished prod-
Table 2 (continued)
uct availability as a pre-filled syringe makes Copaxone® a

Diprivan®
Zoladex®
Sr. no Product
complex drug product. For better clarity and guidance of

name
generic product applicants, USFDA has published product-

Implant
specific guidance (PSG) for glatiramer. In this guidance, the

USFDA recommends few criteria which are to be fulfilled in
38.
39.
13
order to demonstrate API sameness such as equivalence of the viral spike (S) glycoprotein of SARS-CoV-2 virus which
fundamental reaction scheme, physicochemical properties elicits an immune response to the S antigen thereby protect-
including composition, structural signatures for polymeriza- ing against COVID-19 [68]. There are various characteriza-
tion and depolymerization, and results of biological assays tion challenges of rDNA and mRNA being used as APIs.
[17]. Additionally, related substance characterization like Establishing the identity of such oligonucleotides, purity
peptide-related impurity analysis and non-clinical immu- profiling, and analyzing their impurity for related substances
nogenicity assessment of impurities, along with function- are a challenge in developing such products [63].
ality testing of packaging components and other routine
testings, is also required for the successful filing of generic Iron complexes
glatiramer prefilled syringe–based drug product [63]. On the
similar grounds, goserelin acetate, a decapeptide, has been The iron sucrose product of AM Regent, V enofer®, is avail-
formulated into PLGA microspheres by AstraZeneca and is able as an intravenous injection. This product was approved
commercially available as Z oladex®. It is a gonadotropin- enofer®
as an NDA in 2000 for its use as a hematinic agent. V
releasing hormone indicated for the treatment of prostate is a complex of polynuclear iron (III)-hydroxide in sucrose
cancer, endometriosis and in palliative therapy for breast [23]. For generic product approval, PSG recommends to prove
cancer [52]. the API sameness of the test product with the reference prod-
There are various hormone-based injectable products uct. The guidance recommends evaluation of physicochemi-
approved by the USFDA such as Aveed™ and Humulin R. cal properties of this drug product by characterization of the
Aveed™ is a testosterone undecanoate–containing sterile iron core, composition of carbohydrate shell and its surface
oil-based injection used for intramuscular administration. properties, particle morphology, and determination of labile
It was developed by Endo Pharms Inc. and seeked USFDA iron under relevant physiological conditions [69]. Another
approval in 1953. Humulin R is a Lily product approved by iron product, Feraheme™ injection composed of active
the USFDA in the year 1982. It is a regular human insulin ingredient ferumoxytol, was launched by Covis Pharma
produced by the rDNA technology for the treatment of dia- and was approved in 2009 [16]. Feraheme™ infusion is
betes and is administered subcutaneously or intravenously. indicated to treat iron deficiency anemia in adult patients
Despite these established products in the market, hurdles with chronic kidney disease [16]. The semi-synthetic carbo-
at multiple facets from manufacturing to clinical setting hydrate shell confers the complexity of the product-coated
and marketing make the entire development process of new super-paramagnetic iron oxide nanoparticles. These are fur-
generation peptide and hormonal therapy very challenging ther suspended in an isotonic, neutral pH solution admin-
[64, 65]. istered at a relatively high dose by rapid intravenous injec-
tion [70]. A recently approved iron complex by AM Regent
rDNA and mRNA technology is Injectafer® which got approval in 2013 [18]. The active
ingredient of this product, ferric carboxymaltose, is a col-
The rDNA and mRNA technology is used in gene therapy to loidal iron (III) hydroxide in complex with carboxymaltose.
cure/treat/prevent diseases by replacing the defective gene This carbohydrate polymer helps in the release of iron [71].
with a normal one [58]. It additionally enables the defined These complexes are characterized for their X-ray diffrac-
manufacturing of antibodies and proteins with accurate tion, X-ray crystal structure, and NMR and IR spectroscopy.
specificity and uniformity, but the process itself contrib- Also, cyclic voltammetry is used to examine the electronic
utes to the complications in this technology [66]. Eli Lilly property of the synthesized product [72].
and Company’s Forteo™ is an rDNA origin teriparatide
subcutaneous injection approved in the year 2002. It con- Antibodies
tains a recombinant human parathyroid hormone with an
identical sequence to the human parathyroid hormone [17]. Monoclonal antibodies (mAbs) are synthetically developed
Similarly, a product containing PEGylated interferon alpha- antibodies resembling the endogenous moieties. These anti-
2a is developed using rDNA technology by Hoffmann-La bodies seek out and bind to specifically selected proteins
Roche Inc. and is marketed as Pegasys®. It is an antiviral in the body and bring about the immunogenic effect [73].
drug product prescribed for the treatment of chronic hepa- Kimmtrak®, a mAb product developed by Immunocore Ltd.,
titis C [67]. Comirnaty® developed by Pfizer-BioNTech is recently got the USFDA approval in 2022. The active moi-
the first mRNA vaccine approved by the USFDA in 2021 ety Tebentafusp-tebn is a bispecific gp100 peptide-HLA-
for the treatment of COVID-19. It is a sterile lyophilized directed T cell receptor CD3 T cell engager employed for
suspension which is to be diluted with sterile 0.9% sodium the indication of uveal melanoma. Similarly, Cinqair® is
chloride injection, USP before intramuscular administration. a humanized interleukin-5 antagonist mAb (IgG4 kappa)
The active moiety is a nucleoside-modified mRNA encoding indicated for the treatment asthma. This Teva Respiratory
13
LLC product, composed of reslizumab, produced by rDNA the drug release, pharmacokinetic profiles, drug solubility,
technology, seeked USFDA approval in the year 2016. Both formulation stability, and likewise (Fig. 3). However, the
Kimmtrak® and Cinqair® are supplied as a solutions in sin- formulation containing such excipients needs additional
gle-dose vial and are administered intravenously as infusion characterization tests to investigate the functionality of the
[74, 75]. dosage form. Regulatory agencies are also keen to review
information about the toxicity of these novel specialized
Antimicrobial peptides excipients [78].
Antimicrobial peptides (AMPs) are oligopeptides used

against a broad spectrum of organisms. They vary in num- Surfactant and oils
ber from about five to over hundreds of amino acids. AMPs
are generally classified based on their target viz, antiviral Surfactants and oils are extensively used in pharmaceuti-
peptides, antibacterial peptides, antifungal peptides, and cal formulations for varied reasons, such as improving drug
antiparasitic peptides. Fuzeon® developed by Roche is one solubility, stability, and the rest. Surfactants are amphiphilic
such example of antiviral peptides. Enfuvirtide is the active molecules having hydrophilic and hydrophobic functional
pharmaceutical ingredient of this injectable product. It is groups (hydrocarbon chain). Nanosuspension-based drug
composed of naturally occurring l-amino acid residues and products employ surfactants to stabilize the nanosized drug
is a linear 36-amino acid synthetic peptide. It is a lyophilized particles in the colloidal dispersions [79]. Surfactants and
powder which is to be reconstituted with sterile water for oils also play a critical role in formulating injectable emul-
injection prior to subcutaneous administration [76]. Simi- sions. The oils enhance the solubility and dissolution rate
larly, Vancocin is a vancomycin-based injection for intra- of poorly soluble drugs, whereas surfactants help to achieve
venous use. The product developed by Baxter Healthcare is thermodynamic equilibrium between water and oils forming
composed of tricyclic glycopeptide antibiotic drug derived oil–water interface [80]. Surfactant molecules help stabilize
from Amycolatopsis orientalis and is categorized under anti- the colloidal system by reducing the interfacial tension and
bacterial peptides [77]. creating an interface with minimum free energy. Moreover,
use of ionic surfactants increases the stability because of
Complex excipients electrostatic repulsion induced by the surface charge [81].
Similarly, self-emulsifying systems are composed of oils,
Excipients are a critical component of any drug product surfactants, and co-surfactants, which form an emulsion on
development as they are meant to provide desirable charac- mixing with water and need little to no energy input [82].
teristics. In the last few decades, technological advancement Various oils like Miglyol 812, Captex 355, Labrafac, cot-
has led to the development and usage of various functional- tonseed oil, soybean oil, and corn oil are commonly used
ized complex excipients to provide special physicochemical for preparing emulsions and self-emulsifying systems.
properties to the finished products. These excipients enhance Similarly, compounds like sulfates or ester sulphonates,
Fig. 3 Multifaceted viewpoints

involved in the evaluation
of complex excipients for
the development of complex
injectables
13
quaternary ammonium salts, ethylene, propylene oxide, primarily composed of various fatty acids such as palmitic
sorbitan esters, and ethoxylates are widely used as sur- acid, stearic acid, oleic acid, linoleic acid, and linolenic acid
factants [83]. [87]. As the selection of various lipidic combinations and
Paliperidone palmitate is an atypical antipsychotic drug their purity directly affects the product’s quality and perfor-
indicated for the treatment of schizophrenia. Various pali- mance, the FDA expects the applicant to provide detailed
peridone-loaded extended-release suspension drug products information about the origin, distribution, and content of
are approved by Janssen Pharmaceutica NV with different the lipid component in the drug product [88]. For example,
dosage regimens, i.e., once in a month (Invega S ustenna®) in the Product Specific Guidance issued by the USFDA for
[31], once in 3 months (Invega Trinza®) [32], and once Doxil®, the generic drug manufacturer has to develop the
in 6 months (Invega Hafyera™) [30]. These products are drug product by obtaining the lipids from the same category
administered through the intramuscular route (I.M.) and of synthesis route. The lipids used in the manufacturing of
contain polysorbate 20 as a surfactant. Polysorbate 20 plays Doxil® are HSPC, N-(carbonyl-methoxypolyethylene gly-
a pivotal role in stabilizing these suspensions, comprising col 2000)-1,2-distearoyl-sn-glycero3-phosphoethanolamine
of poorly aqueous soluble API dispersed in an aqueous phase sodium salt (MPEG-DSPE), and cholesterol [45].
[84, 85].
Polymers
Lipids
A wide range of polymers has proven their application in
In the last few decades, various lipidic formulations like the development of pharmaceutical products due to specific
liposomes, solid lipid nanoparticles, lipid emulsions, and functions. Polymers act as solubility enhancers, formulation
cubosomes have gained attention among researchers and the stabilizers, and coating agents, which helps in improving
pharmaceutical industry for effective drug delivery. These the overall effectiveness of the formulation. Moreover, few
formulations require lipids as a potential functional excipi- polymers also provide an opportunity for functionalizing tar-
ent to impart desirable properties to the product. Lipidic geting ligands on their surface for the site-specific targeted
excipients enhance the solubility of lipophilic drugs with delivery of therapeutic moieties. Attributed to these proper-
high log P, which are poorly water-soluble. These excipi- ties, polymers are used in numerous novel drug formula-
ents have also been reported to improve permeability of tions imbibing desirable properties [89]. The long-acting
hydrophilic drugs by incorporating them in lipid matrices formulations of various polymers benefit by administering
[86]. These lipids are endogenous as they are structural lower drug doses relative to the daily oral regimen, improv-
and functional components of cell membranes. Common ing patient compliance and convenience.
phospholipids like egg phosphatidylcholine, hydrogenated Formulations composed of poly (lactic-co-glycolic acid)
soybean phosphatidylcholine (HSPC), glycerophospho- (PLGA), a biodegradable co-polymer consisting of lactic
choline, soybean lecithin, and likewise are used to develop acid and glycolic acid, provide a long-term drug release with
lipid-based injectable products (Fig. 4). These lipids are reduction of dosing frequency. It is one of the most widely
Fig. 4 Structure illustration of

various lipids used in complex
injectables products
13
used type of polymer and is available in a linear form and as PEG are used to modify surfaces of nanocarriers to further
a star-shaped glucose (PLGA-Glu) moiety that is structur- improve its pharmacokinetic property and enhance its thera-
ally non-linear. The linear arrangement of PLGA is highly peutic efficacy [95].
hydrophobic and has a low loading capacity in its linear
form [90]. Compared to the linear form, the star-shaped form Miscellaneous/other excipients
has a three-dimensional branched structure. It possesses less
solution viscosity, smaller hydrodynamic radius, higher drug Various other specialized excipients, such as chelating
loading, and drug encapsulation efficiency, encouraging its agents, stabilizers, and likewise, are also categorized under
usage in formulation development (Fig. 5). For example, complex excipients as they impose unique characteristics
in manufacturing of Sandostatin long-acting release inject- to finished products [78]. Also maintaining the physiologi-
able formulation, PLGA-Glu polymer is utilized having cal properties such as tonicity, osmolality, and pH, should
a L/G ratio of 55:45 [91]. However, the characterization be considered while formulating/reconstituting parenteral
of non-linear PLGA with respect to its molecular weight, products. Excipients such as tonicity agents help keep up
lactide:glycolide ratio, and morphology of PLGA is tedious the tissue compatibility at the site of administration. Tonicity
due to shortcomings in analytical methods, contributing to agents are either admixed during I.V. infusion or are added
the complexity of using the polymer [92, 93]. to the formulation if it is to be administered prior to dilu-
Other polymers such as N-(2-hydroxypropyl) meth- tion in a suitable isotonic solution. Sodium chloride, man-
acrylamide, polyamidoamine, polyethylene glycol (PEG), nitol, dextrose, sucrose, etc. are some of the commonly used
poly(glutamic acid), dextrin, dextran, PEI, chitosan, tonicity agents. These agents are also used to reconstitute
poly(aspartamides), and poly(l-lysine) are employed as car- powder for injection when required. Other than maintain-
riers for conjugation with therapeutic moiety to improve its ing physiological conditions, excipients are also employed
pharmacodynamic and pharmacokinetic properties [94]. to modify the release profile and improve physical stability
These are used to conjugate either with small molecules or of the drug products. The release profile of the drug from
with proteins and peptides. Naturally occurring biological the injectable dosage forms depends on the viscosity of the
polymers like albumin are also used for developing formula- formulation. The intermolecular forces between drug and
tions of various therapeutic moieties. Abraxane®, paclitaxel different excipients can further modify the overall viscos-
nanosuspension approved in 2005, is one such complex ity of the formulation; hence, it becomes critical to account
injectable product where albumin is chemically bound to for this parameter. Various viscosity modifiers like sodium
paclitaxel and showed improved therapeutic responses as CMC, xanthan gum, and dipicolinic acid are used to serve
compared to conventional product (Taxol® injection) [28]. this purpose [96].
Additionally, certain amphiphilic polymers like Vfend® is a powder for solution for infusion of voricona-
cetyldimethicone coplyol (Abil EM 90), polysiloxane, and zole developed by PF Prism CV in 2002. Voriconazole is
poly-glycerol-poly-ricinolate are employed as stabilizers for slightly soluble in aqueous conditions over an acceptable pH
various emulsion, double emulsions, and suspensions. These range. Therefore, V fend® was developed using novel cyclo-
polymers adsorb on the external interface of the globule and dextrin-based excipient, sulfobutyl ether beta-cyclodextrin
cover them leading to steric hindrance between the globules (SBE-β-CD), which enhances the aqueous solubility of
and thereby stabilizing the system. Also, polymers such as voriconazole. Inclusion complex formation of voriconazole
Fig. 5 Frame work of PLGA

copolymer. a Linear structure
and b branched structure
13
with SBE-β-CD helps achieve the desired solubility, which commercial success paved the way for these dosage forms in
is usually not possible with conventional pharmaceutical clinical applications. The drug substances delivered through
approaches [97]. OptiMARK™, manufactured by Liebel- these multifunctional carrier system provide controlled drug
Flarsheim Company LLC, is a solution for injection of gado- release with better clinical outcomes [100]. However, there
versetamide, which is a contrast medium for magnetic reso- exists a major gap in scalability of these products because of
nance imaging. Gadoversetamide is a chelate of gadolinium the complexities involved in its design, characterization, and
and a novel excipient versetamide which acts as a stabilizer large-scale manufacturing. Thus, these products require spe-
[98]. cial attention during regulatory approval to ascertain their
Since these novel excipients are used to address specific safety and efficacy.
formulation issues, the developed products require exten- Another challenge related to the manufacturing of com-
sive characterization to demonstrate drug product effective- plex drug products intended for parenteral route is the steril-
ness and excipient functionality for successful regulatory ity of the finished dosage form. Aseptic processing facilitates
submission. the manufacturing of sterile parenteral drug product wherein
the components, such as polymers, lipids, organic solvents,
Complex dosage forms and aqueous buffers, used are sterilized by filtering them
through 0.22-µ pore size filters. Subsequently, these compo-
Most of the drugs existing in market possess undesirable nents are utilized for the preparation of drug products on the
properties like low solubility, short half-life, high protein working stations located in the clean rooms (class-100 area).
binding, and extensive first-pass metabolism, thereby lim- Aseptic filling should be critically monitored for potential
iting their therapeutic activity and overall pharmaceutical sources of contaminants such as primary packaging material,
application. In the last few decades, advanced drug deliv- operating personnel, environmental air contamination, and
ery systems like nano-suspensions, nano-emulsions, and water drainage systems. Considering the unique chemical
other carrier systems like liposomes and microspheres have composition and physicochemical properties of the com-
been explored by pharmaceutical researchers to improve ponents involved in manufacturing of complex injectables,
clinical outcomes of therapeutic agents through parenteral commonly used sterilization techniques (like autoclaving,
route of administration [99] (Fig. 6). Approval of the first gamma radiation, and ionizing radiation) could be detri-
nanotechnology-based drug product, Doxil®, in 1995, and its mental to the stability of finished drug products [101]. The
Fig. 6 Length scale showing the size of the various complex injectable dosage forms
13
manufacturing of these products often involve the use of in 1995. This product based on the Stealth® technology is
biomaterials such as lipids or polymers in combination with proven to be highly effective for treating ovarian cancer,
surfactants and certain ligands for targeted delivery. These AIDS-related Kaposi’s sarcoma, and multiple myeloma,
excipients should be biodegradable, biocompatible, and suit- and minimizing cardiotoxicity associated with doxorubicin.
able with respect to hemocompatibility, histocompatibility, The improved therapeutic effect can be attributed to its glob-
carcinogenicity, genotoxicity, and cytotoxicity. ule size and surface characteristics, which facilitate passive
targeting of drug to the tumor site [105]. For the develop-
Liposomes ment of the generic version of this liposomal formulation,
USFDA has published a PSG, which provides information
Liposomes are novel carrier systems for drugs and are com- on in vitro, in vivo, and physicochemical characterization
posed of one or more lipid bilayer membranes surround- as needed for its successful filing and approval. Some of
ing discrete aqueous compartments. These carrier systems the critical physicochemical characteristics as recommended
can encapsulate the hydrophilic drugs in the aqueous com- in Doxorubicin PSG are liposome composition, state of
partment and lipid-soluble drugs within the lipid bilayer encapsulated drug, internal environment, morphology,
membrane. Liposomes serve the advantage of improving number of liposomal lamellae, lipid bilayer phase transi-
the pharmacokinetic properties of the drug molecule lead- tions, size distribution, grafted PEG at the liposome surface,
ing to lower doses and dosing frequency, site-specific drug electrical surface potential or charge and in vitro leakage,
delivery, and thus improved patient compliance towards the and so forth [106]. Few generic companies like Sun Phar-
therapy [102]. Various technologies have been developed maceutical Industries Ltd., Dr. Reddy’s Laboratories Ltd.,
for the preparation of clinically and commercially viable and Zydus Worldwide DMCC have already received the
liposomal-based products with particle sizes ranging from approval of generic doxorubicin liposomes. In recent years,
50 nm to 50 µm [103, 104]. Electron microscopic images few more products based on S tealth® Technology are either
demonstrating the morphological structure of different tech- under development/approval stage or have seeked approval
nology-based commercially approved liposomal products are for commercial purpose. Ipsen Biopharmaceuticals Inc.
shown in Fig. 7. received a USFDA approval in 2015 for the irinotecan lipo-
Stealth® technology utilizes the conjugation of nano somal injection, O nivyde®, which is also based on similar
liposomes with globule size of 100–200 nm with polymers technology [47].
like PEG to provide nano-sized vesicular systems with pro- In the last couple of decades, D epoFoam ® technol-
longed blood circulation. Doxorubicin-loaded PEGylated ogy–based liposomes, i.e., multivesicular liposomes (MVL),
liposome, marketed as Doxil® by Janssen Pharmaceuticals are also gaining scientific attention for sustained delivery of
Inc., was the first nanotechnology-based product approved therapeutics. This delivery system contains a non-concentric
Fig. 7 Electron microscopy of liposomes. a Unilamellar Nanoli- from Elsevier). b Multivesicular Liposomes (scale = 2 µm) (Reprinted
posomes (scale = 100 nm) (Reprinted from International Journal of with permission from Langmuir, 1996, 12(20), Spector MS, Zasa-
Pharmaceutics, 2018, 547(1–2), Damari SP, Shamrakov D, Varenik dzinski JA, Sankaram MB, Topology of Multivesicular Liposomes,
M, Koren E, Nativ-Roth E, Barenholz Y, Regev O, Practical aspects a Model Biliquid Foam, Pages No. 4704–4708. Copyright © 1996
in size and morphology characterization of drug-loaded nano- American Chemical Society)
liposomes, Pages No. 648–655. Copyright © 2018, with permission
13
core that facilitates the controlled release of drugs at the MVL. The gradual erosion of the vesicles within the MVL
site of action. Usually, these delivery systems are in the over a period of time results in diffusion of the drug for a
micron size range, with a median diameter of 20–30 µm prolonged period (Fig. 8). Manufacturing of MVL in aseptic
[107]. Depofoam® technology has been successfully trans- conditions aggravates the complications in developing this
lated for commercial application by Pacira Pharmaceuticals product. USFDA has published PSG for the generic appli-
with products like Depocyt®, DepoDur®, and E xparel®, for xparel®, which recommends establishing sameness
cant of E
sustained delivery of cytarabine, morphine and bupivacaine, of API and lipid excipients. It also highlights the agency’s
respectively [108, 109]. Based on the commercial applica- expectation of performing bioequivalence studies as a two-
tions of MVL, various products have been developed to way crossover in vivo experiment for the test product in
deliver small and large molecules, which are under the pre- comparison to reference product. Other physicochemical
clinical and clinical trials [110]. MVL preparation is a highly properties like liposomal composition, internal aqueous
complex multistep process with adequate control of quality environment, globule structure and morphology, and in vitro
attributes like globule size, internal volume, drug encapsula- drug release rates are some of the critical parameters which
tion, and desired release characteristics. MVL is composed are to be characterized for successful development of generic
of synthetically modified naturally occurring lipids that bupivacaine liposomes [107]. The thermosensitivity of this
are biocompatible and biodegradable in nature. This drug product can clearly be understood from the stability testing
delivery system is different from unilamellar/multilamel- studied by the innovator where the testing was conducted at
lar liposomes in that it consists of honeycomb-like internal 5 ± 2℃ (long-term) and 25 ± 2℃ (accelerated) along with
structure of non-concentric lipid bilayers encapsulating a non-conventional intermediate conditions of 15℃. Because
significantly higher amount of drug. The drug release from of thermo-sensitivity, this product comes with a temperature
the MVL is initiated by the breakdown of the outermost indicator in its packaging to indicate any thermal degrada-
vesicles leading to the redistribution of the drug within the tion during shipment [111].
Fig. 8 Schematic representation of multivesicular liposome (MVL) S, Singh AK, A review on multivesicular liposomes for pharmaceuti-
structure (Reprinted by permission from Drug Delivery and Transla- cal applications: preparation, characterization, and translational chal-
tional Research, 2021, Chaurasiya A, Gorajiya A, Panchal K, Katke lenge. Copyright © 2021, with permission from Springer Nature)
13
Polymeric particles indication of schizophrenia. Both Invega® Sustenna™ and

Aristada™ are sterile aqueous–based extended-release
In the last few decades, PLGA-based products have proven injectable suspensions available as pre-filled syringes for
their application in the sustained delivery of various drugs intramuscular administration [29, 31].
by the parenteral route of administration. Octreotide is a Nanosuspensions are colloidal dispersions having parti-
long-acting octapeptide with pharmacologic properties cle size ranging from few nanometers to 5 µm. They can be
similar to natural hormone somatostatin. An injectable sus- manufactured in aseptic and non-aseptic conditions based
pension composed of octreotide microspheres comprises on particle size and sensitivity towards sterilization process.
a biodegradable glucose star polymer, and d- and l-lactic Most of these nanosuspension products are thermolabile
and glycolic acid co-polymer. This formulation, marketed in nature which limits the choice of sterilization method.
as Sandostatin LAR® Depot by Novartis Pharmaceuticals As per sterilization decision tree published by the Euro-
Corp., received its USFDA approval on Nov 25, 1998. For its pean Medicine Agency, autoclaving is the most preferred
generic product development and regulatory filing, USFDA method of sterilization of injectable products followed by
has published PSG highlighting the requirements for single- sterile filtration and aseptic processing/filling [116]. Steri-
dose, parallel design in vivo bioequivalence study of test lization using filtration technique is not feasible always as
product in comparison to reference product [112]. Similarly, certain products have particle size of more than 0.2 µm. In
Risperdal Consta®, a long-acting injection of risperidone such cases, the only option left to render sterility in finished
PLGA (75:25) microspheres for intramuscular administra- product is aseptic processing and filling. In aseptic process-
tion, is employed for the treatment of schizophrenia and ing, all manufacturing activities starting from compounding/
bipolar I disorder. Janssen Pharmaceuticals Inc. received mixing with the formulation vehicle, particle size reduction,
approval from the USFDA for this pharmaceutical product in final volume make-up, filling, and sealing into the primary
2003 [38, 113, 114]. In a different product, a synthetic nona- packaging are carried out under sterile conditions. Addi-
peptide analog of naturally occurring gonadotropin-releas- tionally, manufacturing of these products in aseptic condi-
ing hormone (GnRH), leuprolide acetate, was formulated tion need more considerations with respect to selection of
into lyophilized PLGA microspheres and is commercially excipients, method, and scale-up activities. Quality control
marketed by AbbVie Inc. as Lupron D epot® (depot suspen- testing of these products include assay, particle size, impu-
sion). Besides the use of synthetic polymers for preparation rity determination, density, viscosity, bioburden, sterility,
of intravenous particulate systems, there have been a few dissolution, etc.
which are formulated using naturally occurring polymers/
braxane® is one such particulate
proteins like the albumin. A Emulsions
product composed of paclitaxel bound to albumin protein
with a mean particle size of about 130 nm. This Abraxis The injectable emulsion-based formulation has proven to
Bioscience product attained USFDA marketing approval in be a successful approach for hydrophobic drug delivery.
the year 2005. Abraxane™ is available as a sterile lyophi- Many products are developed and have received regulatory
lized powder which is to be reconstituted with 0.9% sodium approval for commercial and clinical applications [117].
chloride injection, USP, and is administered as intravenous Propofol injection ( Diprivan®) is oil-in-water emulsion mar-
suspension for the treatment of breast cancer [28]. keted by Fresenius Kabi USA LLC as a general anesthetic
by intravenous administration [51]. It is prepared using a
Suspensions combination of high shear and high-pressure homogeniza-
tion methods. Similar to propofol, clevidipine shows poor
Suspensions are dosage forms used to deliver drugs which aqueous solubility and is formulated as an injectable for-
are less soluble or insoluble in water or a solvent system mulation for I.V. administration. Clevidipine emulsion for
suitable for administration as a solution. Also, when the use injection is marketed as Cleviprex® by Chiesi USA Inc.
of solubilizing agents for such drugs does not improve its [50]. For successful filing and approval of such emulsion-
solubility, suspensions become the choice of formulation based products, it is essential to develop a robust process to
to deliver these active moieties [115]. Invega® Sustenna™ manufacture uniform-sized globules. Characterization with
is a pharmaceutical injectable suspension developed by respect to globule size, surface charge, emulsion stability,
Janssen Pharms for the delivery of paliperidone palmitate. drug content, and so on is required to be carried out in a
This product got its USFDA approval in the year 2006 for meticulous manner.
the treatment of schizophrenia. Another recently approved The PSG of propofol recommends two-way crossover
extended release suspension is Aristada™. This aripipra- design bioequivalence studies for the development and filing
zole lauroxil–containing product developed by Alkermes of its generic product. The USFDA confers a provision of
Inc. seeked its USFDA approval in the year 2015 for the bio-waiver for qualitative and quantitative (Q1/Q2) similar
13
products with acceptable physicochemical characteriza- labeling, and packaging. Here are some specific require-
tion, population bioequivalence studies, and in vitro release ments needed to be considered by applicants for the success-
between the test and reference product [118]. ful development and approval of these complex drug-device
combination products.
Injectable implants
General information
In last few decades, injectable implants have gained attention
as they possess several advantages like controlled and con- The applicant must include usage information of the pro-
tinuous release of drugs up to several weeks/months. Bio- posed drug-device combination, including the site and depth
degradable polymers could be utilized to develop injectable of injection, and type of use (single, reusable, disposable,
implants because of their biocompatible nature and natural or refillable injector). Detailed description about conditions
metabolic pathways. Of the various biodegradable polymers of use should be mentioned, including the injection method
identified, PLGA has been widely explored to develop drug- (manual, piston, spring load, gas, jet), details about the dose
loaded injectable implants. A commercially available inject- such as single dose or multiple and adjustable dose, envi-
able implant Zoladex® is a sterile, biodegradable product ronmental storage conditions, and handling of the pre-filled
containing goserelin acetate dispersed in PLGA, adminis- injectors [123].
tered by subcutaneous route [52].
Device design
Drug‑device combination products
The design features of the pen device or auto-injector should
Delivery of drugs through parenteral routes such as intra- be included in the submission documents. Detailed informa-
muscular (I.M.), subcutaneous (S.C.), and intravenous (I.V.) tion on the technical specifications of the injector and its
is chosen when the drug molecules show degradation in the characteristics is a prerequisite [123]. The applicant needs to
gastro-intestinal milieu or nasal tissues. However, parenteral generate data comparing the design features of their injector
routes of drug delivery suffer from disadvantages such as to the parts of the injector in a similar approved product. The
the requirement of skilled healthcare professionals for the applicant is also expected to provide drawings of the engi-
administration of the drug product. Moreover, frequently neering components, injector photographs, and stages show-
dosing drugs with a short half-life (small molecules/pep- ing the drug product delivery. Figure 9 illustrates the basic
tides) for treating chronic diseases generate serious patient design and components of these devices. The drug prod-
non-compliance [119]. Therefore, efforts are being made by ucts are stored in barrel/cartridges made up of compatible
the pharmaceutical industries for the development of drug material like glass, polypropylene, cyclic olefin copolymer,
delivery devices to improve patient compliance and over- and packed with plunger. The FDA recommends providing
come the barriers in parenteral drug therapy. Drug device information on procedures for setting the required dose using
systems such as pre-filled syringes (PFS), injector pens, mechanisms such as a dial, assembling the injector, prepar-
and similar have made parenteral drug administration rela- ing and positioning for an injection, resetting the quantity
tively easy and patient-friendly [120]. To ensure the safety, after use, and changing or disposing of the needle. These
convenience, reduction of dosage errors and waste, proper requirements are meant to assure the ability of the injector to
labeling, drug product sterility, and stability, most regulatory be reliable and reproducible for delivering the drug product
agencies have laid down specific requirements and expec- with desired injection volume to the target tissue. The guid-
tations for the approval of such drug-device combination ance also suggests using graduation marks and fill lines to
products [121]. Products such as EpiPen® and EpiPen Jr® are help the user set the correct dose or verify the set dose along
examples of pre-filled auto-injectors which are indicated for with a feature of visual inspection of any particulate matter
emergency treatment of allergic reactions and anaphylaxis. within the product.
Also, Invega® Sustenna™ is provided in a prefilled syringe
(cyclic-olefin-copolymer) with a plunger stopper and tip cap Drug‑device interaction
(bromobutyl rubber) [15, 31].
Regulators like USFDA and EMA have issued a guidance FDA expects the manufacturer to include information about
document describing the scientific and technical information the materials used in the construction and manufacturing of
to be considered by the manufacturer when developing a the injector devices. During the development of drug-device
pen, jet, or related injector device meant for administration combination products, the interaction between the material
of a drug or a biological formulation [122]. The regulatory of construction of the injector with the drug or biological
requirements for the injectors or pen devices differ depend- product needs to be evaluated and supported with stability
ing on their intended use, product characteristics, proposed data [123].
13
Fig. 9 Various components of injection devices. a Auto-injector pen device; b pre-filled syringes
Device safety features Labeling requirement
To prevent injury and ensure accurate dosing, it is recom- Pen, jet, or injector devices are meant for direct use by
mended to incorporate certain safety features into the injec- the patients, caregivers, or healthcare professionals. The
tor device. These safety features may include audible, visual, USFDA recommends developing the labels in consideration
and tactile notifications, switches, or mechanical protection. with the end-users and suggests including package insert
The manufacturer should also consider human factors while for the instructions on how to use the injector safely and
designing the injector device, such as the age of the tar- effectively [123].
get population, tissue characteristics at the site of admin-
istration, limitations due to visual impairment, or manual
dexterity. Characterization tools for complex
injectables
Device performance testing
Typically, complex injectable products are comprised of
As a component of general testing, FDA recommends the unique physicochemical properties which facilitate their
applicant to conduct performance testing of the devices. For functionality. Therefore, to successfully develop and trans-
the submission, general testing includes the test for dose late complex injectable formulations, it is necessary to
accuracy, demonstration of the depth of needle penetration, identify and use suitable characterization tools/techniques
and accurate dispersion of drug product at the target site. to evaluate their physicochemical properties. Proper charac-
Special tests for evaluation of extractables, leachables, and terization ensures the therapeutic efficacy and safety profile
absorbables, along with tests for container-closure integ- of these developed formulations. Generally, these formula-
rity and shelf-life dating, are recommended to be submitted tions are characterized for particle size, morphology, sur-
[123]. FDA has also provided a guidance document for the face characteristics, drug content, entrapment efficiency, and
assurance of sterility of injectors [124]. Table 3 summa- others [125]. In this section, various tools and techniques
rizes the list of various tests as needed for seeking regulatory commonly used to evaluate the characteristics of complex
approvals of prefilled syringe-based products. injectable products are discussed. For better understanding,
13
Table 3 Compendial tests for pre filled syringes (PFS) as per ISO 11040–4
Sr. no Test Rationale
1. Flange breakage resistance While delivering the dose, most of the force is applied on plunger and barrel flange.
Thus, it should be rigid to withstand the force
2. Luer cone breakage resistance Luer cone is the assembly, where the needle is fixed by applying some torque. This
test thus proves the ability of the luer to withstand the torque which is applied
while attaching the needle before dose administration
3. Break loose and glide force Break loose: it is the initial max force applied during administration
Glide force: it is the average force required for completing the dose administration
4. Needle penetration test and Needle pull out force For any stacked needle PFS, while administration practitioner has insert PFS into
the vial stopper. It takes some force to penetrate and pull out. This force should be
within the limit of manufacturer and end user requirements
5. Luer lock adaptor collar pull-off force Luer lock adapter is fixed on PFS barrel tip which requires certain force to be
removed. Limits are thus correspondingly fixed based on the manufacturer and
end user
6. Closure system liquid leakage test This test is performed to confirm sterility of injectable products
7. Luer lock adaptor collar torque resistance Torque is applied while applying/removing the needle to luer lock. Thus, the
adaptor should stay stiff and not be rotated while applying torque during screwing
and unscrewing
8. Luer lock rigid tip cap unscrewing torque Torque is applied while applying/removing the needle to luer lock. Thus, the
adaptor should stay stiff and not be rotated while applying torque during screwing
and unscrewing
9. Pull-off force of the tip cap or the needle shield For PFS stacked needles, those were supplied with plastic rigid cap with elastomer
10. Dye solution tightness test This test is performed to confirm sterility of injectable products
we have summarized common characteristics required to be is commonly used to measure particle size (z-average, D10,
evaluated along with the tools in Table 4. D50, and D90) and polydispersity index (PDI) of various
nanosized formulations like liposomes, nanosuspensions,
Size and shape/morphology nano-emulsions, and other similar products. Commercially
available instrument for the measurement of particle size
Particle size and shape/morphology have a significant role through DLS technique is a Zetasizer suitable for measure-
in determining the stability of the particulate formulation ment of particle size ranging from more than 1 nm to less
(micro- or nano-size range) [151]. They also affect the phar- than 1 µm. Zetasizer instrument is developed and marketed
macokinetics and pharmacodynamic behavior of the drug by the company Malvern Panalytical Ltd.
substances [152]. Particle size measurement is needed to
conduct population bioequivalence for complex generic Laser diffraction analysis
product development and subsequent approvals [106]. These
measurements can be done by various available techniques Laser diffraction analysis, or laser diffraction spectroscopy
with their different principle for the diverse range of the technique, is based on the measurement of angular changes
complex injectable products, as discussed below. in the intensity of scattered light [155]. The degree of scat-
tering of light and particle size is inversely related to each
Dynamic light scattering other. Red and violet lasers are used to analyze large and
sub-micron-sized particles, respectively [156]. Mastersizer,
Dynamic light scattering (DLS) is one of the widely used marketed by Malvern Panalytical Ltd., is based on this tech-
light scattering techniques for particle size measurement of nique and is commercially available for the measurement of
different formulations whose diameter ranges from nano- to particle size ranging from submicron to millimeter.
sub-micron. Measurement of intensity fluctuation due to the
Brownian movement of particles present in a colloidal dis- Field‑flow fractionation
persion system is the basic principle of the DLS technique
[153]. Alternatively, it is also well-known as photon correla- Field-flow fractionation (FFF) techniques measure the
tion spectroscopyor quasi-elastic light scattering technique size distribution and relative molecular mass of samples
[154]. By DLS, average hydrodynamic diameter and distri- [157]. FFF is basically a separation technique where
bution of particle size range can be accessed. This technique semi-permeable membrane filter–based channel wall
13
Table 4 Characterization of Complex Injectable Products

Sr. no Characteristics Characterization tools Complex products Ref
1 Size and shape Dynamic light scattering Liposomes, nanoparticles, [126–132]

Laser diffraction analysis microspheres, emulsions, suspensions
Field-flow fractionation
Electron microscopy
Differential centrifugal sedimentation
Nanoparticle tracking analysis
Small-angle X-ray scattering
2 Surface charge and surface analysis Zeta potential Liposomes, nanoparticles, suspensions, [133–137]
Tunable resistive pulse sensing emulsions
Atomic force microscopy
Brunauere Emmette Teller
Auger electron spectroscopy
3 Morphology and topography Scanning electron microscopy Liposomes, nanoparticles, [138, 139]
Transmission electron microscopy microspheres, emulsions, suspension
4 Material characterization X-ray diffraction Drug substance, peptides, liposomes, [140–142]
Raman spectroscopy nanoparticles,
Atom probe tomography microspheres
5 Thermodynamic characterization Differential scanning calorimetry Drug substance, liposomes, emulsions [143–145]
Differential thermal analysis
Thermal gravimetric analysis
31
6 Lamellarity analysis P nuclear magnetic resonance Liposomes [146]
7 Assay/excipient content analysis High-performance liquid Drug substance, lipid-based product, [147, 148]
chromatography polymer product
Thin layer chromatography
8 In vitro drug release USP dissolution apparatus type 2 Liposomes, nanoparticles, [106, 149, 150]
USP dissolution apparatus type 4 microspheres, emulsions, suspensions
Bottle rotating apparatus
Dialysis Bag
Franz Diffusion Cell, etc
are used to determine the size distribution of particles Atomic force microscopy
[158]. Commercially available instrument for the FFF
technique is Eclipse™, developed and marketed by Wyatt Atomic force microscopy (AFM), also called scanning force
Technology. microscopy, is used for evaluating the surface topographic
image of the particles. In this method, the sample surface
interacts with the instrument’s cantilever and probe (sharp
Electron microscopy tip) assembly to provide a three-dimensional high-resolu-
tion image of a sample [161]. This method can determine
Electron microscopy is used to visualize the micron/nanoparticle shape, size, surface texture, and other topographic
size particles, which helps to study their morphological information. Various types of AFM models are commer-
characteristics [159]. Regulatory agencies recommend cially available by manufacturers like Bruker, Nanosurf, and
evaluation of particles’ external/internal structures like Zurich Instruments. Based on the requirements and features,
internal volume, porosity, and coating thickness. These appropriate model of the instrument can be used for analysis.
characteristics can have a direct/indirect effect on various
mechanisms like drug release, entrapment, stability, and Nanoparticle tracking analysis
the rest. Scanning electron microscopy and transmission
electron microscopy (TEM) are commonly used tech- Nanoparticle tracking analysis (NTA) is a relatively new
niques that facilitate understanding surface morphology technique that can measure particle size (30–1000 nm) of
and the internal structure of particles, respectively [160]. both mono- and poly-dispersed systems [131]. NTA is based
Various types of electron microscopes are commer- on both light scattering and Brownian movement principle.
cially available from companies like Hitachi, Philips, It additionally also uses the Stokes–Einstein equation to
Bruker, and a few others. measure the particle’s average hydrodynamic diameter [162,
13
163]. Nanoparticle tracking analyzers are commercially mar- properties of nanoparticles, like concentration, size, and
keted by Malvern Panalytical Ltd., Microtrac Retsch GmbH, surface charge. This technique can detect particles of size
and Horiba Scientific. ranging from about 50 nm to a few micrometers. Commer-
cially available instruments for TRPS analysis are provided
Small‑angle X‑ray scattering by Izon Science Ltd.
Small-angle X-ray scattering (SAXS) is a flexible and non-

Physicochemical properties
invasive analytical technique used for structural character-
ization. It measures the intensities of the scattered X-ray
Various complex drug substances and excipients possess
beam by the sample as a function of the scattering angle.
unique physicochemical properties, which are majorly
It can measure particles having sizes of 1–1000 nm [164].
responsible for showing desired response and overall per-
SAXS is also used to determine the structure of a drug inside
formance of the complex product. There are different sophis-
oxil®
the carrier system if it is in precipitated form like D
ticated tools/techniques which can evaluate their physico-
[105]. Commercially available models for SAXS analysis
chemical properties.
are provided by Rigaku, Bruker, Malvern Panalytical Ltd.,
etc. Users can select the appropriate model based on specific
requirements and applications. X‑ray diffraction
Surface charge X-ray diffraction (XRD) is a non-destructive technique

used to characterize crystalline materials. It provides valu-
The surface charge of particle-based injectable products able information regarding the arrangement of atoms in the
helps in maintaining the physical stability and interaction crystal lattice, crystal defect, electronic configuration, and so
with the biological membranes. Therefore, surface charge on [168]. XRD can help understand various characteristics
measurement of these particles helps determine their physi- of solid powder (drug substance/excipients) like polymor-
cal, chemical, and biological stability and behavior. phism, degree of crystallinity, amorphous character, and a
few other properties. These can directly affect parameters
Role of zeta potential like drug release, entrapment, and stability. Commercially,
various models of XRD instrument are provided by manu-
The degree and nature of the interaction between particles facturers like Bruker, Rigaku, Malvern Panalytical Ltd., and
can be accessed by the zeta potential (ZP) value. Zeta or Anton Paar. Based on the applications and requirements, the
electrokinetic potential represents the potential at the shear users can select the appropriate model.
plane, which directly impacts the stability of the drug prod-
uct [165]. Usually, a system with a higher ZP value (positive
Raman spectroscopy
or negative) is electrically stable, but a low ZP value leads to
instability [166]. Various instruments based on the principle
Raman spectroscopy is a rapid non-destructive technique
of zeta potential measurement (like zeta sizer, litesizer, etc.)
used to characterize drug formulations’ structural, electri-
are available commercially and used for characterization
cal, and chemical properties [169]. It is based on shifting of
of particulate formulations like liposomes, nanoparticles,
the wavelength of the inelastically scattered radiation [170].
nanosuspension, and other formulations. Zetasizer (Malvern
It can be used to evaluate the chemical composition and
Panalytical Ltd.) is a commercially available instrument for
structure of the sample. This technique helps generate a two-
the measurement of zeta potential through electrophoretic
dimensional chemical image of the sample and visualizes the
mobility.
distribution of drug and excipient in complex formulations.
Commercially available models for Raman spectroscopic
Tunable resistive pulse sensing
analysis are provided by manufacturers such as Anton Paar,
Horiba, and Mettler Toledo.
Tunable resistive pulse sensing (TRPS), also called as scan-
ning ion occlusion sensing method works on the “Coul-
ter counter” principle [167]. In this method, particles are Thermal characterization
allowed to pass through pores of thin membranes, which
causes blockage in the ionic current flow for a short time Thermodynamic characterization is an essential study dur-
and leads to the generation of “resistive pulse.” These pulses ing the design and development of any dosage form since
are detected, and particle population is characterized accord- it provides vital information regarding the phase transition,
ingly. TRPS can be used to measure the physicochemical which affects product stability.
13
Differential scanning calorimetry Lipid/polymer content analysis
Differential scanning calorimetry (DSC) is a thermoana- The analysis of specialized excipients like polymers, lipids,
lytical technique that measures the heat difference required and other excipients is important to predict the stability of
to raise the temperature of the sample compared to ref- the finished product. Various techniques like HPLC, TLC,
erence with the progress of temperature. DSC is used and gel permeation chromatography are used for detecting
to measure the thermal behavior of complex excipients and quantifying levels of these excipients in finished prod-
(primarily lipids, polymers). The phase transition event, ucts [177, 178].
i.e., melting and crystallization (physical transformation)
of the sample, is measured as it undergoes exothermic or In vitro drug release
endothermic reaction [171]. DSC is also used to measure
the glass transition temperature (T g) of a bulk solution The in vitro drug release profile of complex formulations
intended for lyophilization recipe development. Several is a prerequisite to predict the release pattern in vivo and
models of DSC analyzers are commercially available by helps establish the IVIVC model. Various methods and
manufacturers such as Shimadzu, Mettler Toledo, Malvern instruments are available in order to conduct in vitro release
Panalytical, Linseis, and PerkinElmer. Based on the user studies. Generally, USP dissolution apparatus II and IV are
requirements and applications, appropriate models can be commonly used depending on the type of formulation; e.g.,
selected. formulation of octreotide employs the use of USP dissolu-
tion apparatus IV. Additionally, bottle rotating apparatus, an
unconventional method, is also used to determine the release
Differential thermal analysis pattern of liposomes, nanoparticles at various temperature,
and pH conditions [179, 180].
Differential thermal analysis (DTA) is also a thermoana-
lytical technique, where measurement is based on the tem-
perature difference between sample and reference. DTA Commercial equipment used
can provide information on various parameters like phase in the manufacturing of complex injectable
transition temperature, crystallinity, purity, oxidative, and products
thermal stability [172]. Commercially, DTA analyzers are
provided by manufacturers like TA Instruments, Shimadzu, The manufacturing of complex injectable drug products is a
and Mettler Toledo. complicated process which include puzzled manufacturing
scale-up activities and regulatory requirements. Due to the
rapidly growing research in the field of complex injectables,
Thermal gravimetric analysis innovation in the field of equipment development and manu-
facturing is taking a good pace considering the robustness
The thermal gravimetric analysis (TGA) technique is used and reproducibility of the output. In this section, we have
to evaluate thermal stability of sample as a function of the discussed a few commonly used equipment utilized by the
change in its mass at a constant heating rate. TGA can help pharmaceutical industries for the manufacturing of complex
determine information on the physical phenomenon (i.e., injectables drug products.
phase transition, adsorption, absorption, desorption), chemi-
cal phenomenon (i.e., thermal decomposition, chemisorp- Tangential flow filtration assembly
tion), and solid–gas reaction (i.e., oxidation, reduction)
[173]. Numerous models of TGA analyzers are commer- Tangential flow filtration (TFF), also known as “cross-flow
cially available by manufacturers such as Shimadzu, TA filtration,” is commonly used for concentrating and remov-
Instruments, and Mettler Toledo. ing of salts from dissolved molecules such as proteins,
nucleic acids, peptides, and other biomolecules such as car-
bohydrates. In this, the stream of feed passes parallel to the
Lamellarity analysis membrane where one portion passes through it (as permeate)
while the remainder is recirculated back to the feed reservoir
Lamellarity refers to the number of lipid bilayers present in (as retentate) with the help of circulating pumps. TFF is also
the liposomes. It influences entrapment efficiency and drug used for exchanging buffers and gross fractionation which
release kinetics [174]. Lamellarity can be determined by is used in manufacturing of drug products such as liposo-
various techniques like 31P nuclear magnetic resonance (31P mal formulation of D oxil® [181]. Commercially, various
NMR) and Cryo-TEM [175, 176]. manufacturers like Pall corporation, Millipore, Sartorius,
13
and others provide TFF assemblies based on the industrial Regulatory aspects and challenges
requirements.
Injectables administer the active moiety directly into the
systemic circulation or target tissue invading the primary
High‑pressure homogenizer defense layer using a hollow needle and a syringe. The
entire procedure carries considerable risk to patients con-
High-pressure homogenizer (HPH) has been used in pharma- cerning sterility breach, particle contaminations, toxic/
ceutical industries for the purpose of particle size reduction allergic reactions, etc. Considering these risks, regulatory
in micro- to nano-range along with stabilization and mix- agencies take utmost care in approving injectable products
ing of formulation components during the manufacturing of [185]. As discussed earlier, complex injectable products
complex injectable products. It serves characteristic advan- carry surplus toil for its development and manufacturing,
tages as it is a scalable and versatile processing method and is which raises more concerns for their regulatory approval.
being employed in the preparation of different drug delivery Therefore, regulatory agencies expect additional studies
systems such as nanoparticles, nanoemulsions, nanosuspen- during its development, manufacturing, and characterization
sions, nanostructured lipid carriers, and others [182]. to mitigate the associated risks and approve products of the
HPH typically consists of a high-pressure pump and intended quality [186]. Some commercially approved com-
homogenization valve. The high-pressure pump is of posi- plex injectable products include liposomes, nanoparticles,
tive displacement type which is also suitable for highly peptides, microspheres, emulsions, suspensions, and a few
viscous fluids that are usually used in formulating complex others [187]. USFDA has taken specific initiatives to create
injectables. The homogenization valve increases the veloc- guidelines for these complex products to make the regula-
ity of the fluid creating a turbulence leading to breakdown tory filing process facile and streamlined. These guidelines
of the component fluid. HPH belongs to a new generation give the manufacturers an overview of the approach in
of homogenizers wherein it can be operated at pressure lev- order to develop these products, specific tests, and exhaus-
els of up to 400 MPa. Commercially, HPHs are provided tive characterization involved in the product development
by various manufacturers like Microfluidizer® Processors, and means of overcoming existing challenges and concerns.
Avestin Inc., GEA, and Stansted Fluid Power Ltd. The complex nature of liposomes due to their constituents,
thermodynamic nature, and sterility involved is not unknown.
Therefore, the USFDA has published a guideline for the devel-
In‑line high shear homogenizer opment and manufacturing of liposomal drug products [188].
This guideline provides the expectations of USFDA on the
In-line high shear mixers/homogenizers are of particular data needed to be submitted for the approval of the liposo-
importance during large-scale manufacturing of various mal-based product. Table 5 summarizes the requirement for
products like microspheres, suspensions, emulsions, and approval of these products by the USFDA. Doxil® (1995),
similar formulations [183]. In-line homogenizers work on Daunoxome® (1996), A mbisome® (1997), D epocyt® (1999),
rotor–stator technology and the particle size depends on the Myocet (2000), Mepact® (2004), Advate (2009), Exparel®
® ®
homogenization speed. Commercially, Kinematica, IKA, (2011), Marquibo® (2012), L ipodox® (2013), O nivyde®
Silverson, etc. provide various designs of high shear homog- (2015), etc. are some of the marketed injectable liposomal
enizer machines suitable for a varied production require- products. The USFDA has also published PSGs to provide
ments and batch volumes. clarity to generic applicants for the development of these
products. The PSGs provide the agency’s recommendation
on characterization studies and bioequivalence studies for the
Lipid extruder approval of these generic products [189]. A similar regulatory
approach has been devised for injectable formulations like
Extrusion is a technique where the liposomal suspension is nanosuspensions and microspheres. A range of these products
passed under applied pressure through polycarbonate mem- exhibit a plethora of applicability in parenteral administration.
branes [184]. The polycarbonate membranes are of a par- Various nanoparticle-based products like A braxane® (pacli-
ticular pore size designed to obtain unilamellar liposomes of ®
taxel nanoparticles) and Invega Sustenna (paliperidone pal-
homogenous size from a population of heterogeneous multi- mitate injectable suspension), and microsphere-based depot
lamellar liposomes. L IPEX® Flow by Evonik manufactures formulations like Risperdal C onsta®, Sandostatin® LAR
a range of liposome extruders meant for seamless scale-up ®
Depot, Vivitrol , and B ®
yetta have already proven clinical
of the unit operation process from research laboratory to and commercial benefits and thereby are of high interest for
commercial manufacturing. pharmaceutical manufacturers and regulatory agencies [187].
13
Table 5 USFDA guidelines for injectable liposome preparation

A. Chemistry, manufacturing and control of the product:
a Detailed description on product composition API used and its quantity, lipid components, non-lipid components,
buffer components, quantity of each lipid component used in
the final formulation, etc
b Physicochemical properties of the drug product Morphology, particle size, surface characteristics, net charge, viscosity,
phase transition temperature of the product, etc
c Critical quality attributes As per Q8 (R2) ICH guidelines
d Description of manufacturing process and process controls
e Control of lipid components
f Specification of drug product
g Stability data Physical, chemical, and microbiological
h Post approval changes in manufacturing
B. Human pharmacokinetics: bioavailability and bioequivalence:
a Study on clinical pharmacology Pharmacokinetic and mass balance studies for liposomal drug products,
comparison clinical pharmacology studies with non-liposomal drug
product
b Biopharmaceutical study Drug release pattern, IVIVC, use of validated bioanalytical method,
protein-liposome interaction
C Labeling:
a Non-proprietary name for the drug product as per FD&C act
b Description section
c Dose and route of administration
However, generic product development and filing are the tedious manufacturing processes involved. Moreover, the
challenging tasks due to the high complexity involved in its intricacies involved in their accurate characterization add to
manufacturing and bioequivalence studies. The stringent reg- the developmental challenges of complex products. There-
ulatory expectation and lack of proper guidance concerning fore, multistep manufacturing processes, non-conventional
development, manufacturing, and detailed dosage form/poly- quality attributes, and unique characterization tools/tech-
mer characterization add more complications to the overall niques enhance the complexities. Thus, tapping the sameness
development. Additionally, there is a requirement for specific and bioequivalence to the RLD as per the regulatory require-
toxicological studies like mutagenicity and genotoxicity, which ments becomes very critical. Despite these obstacles, there
further complicates the filing process. Regulatory agencies have been many commercially successful products, which
like the USFDA and EMA are very keen on providing clear pave the way for using these technologies in filing innova-
expectations on the development of complex injectables for tor and generic products. The agencies do acknowledge the
fastening the approval process. Providing PSGs is one of the complexities involved in the formulation and encourage the
major initiatives taken by the USFDA, but that is only limited development of these products. Regulatory agencies like the
to the generic applicant, and many times the information pro- USFDA and EMA are creating a support database for filing
vided is also not sufficient. Considering the issues faced by the and approval of such products. They are also trying to cre-
applicants, there is an immediate need to devise an automated ate more transparent and meaningful guidelines, organizing
system that would help them resolve queries during the com- product workshops and training sessions to educate industry
plicated process of product development and approval [190, professionals with real-world evidence and regulatory expec-
191]. tations. Product-specific guidelines published by the USFDA
help the generic applicants streamline their development
and filing processes. It also gives them a provision to waive
Conclusions and future perspectives off in vivo bioequivalence studies based on sound in vitro
experiments. In our opinion, complex injectable products
Complex injectable products involve multi-unit operations, have sparked the pharmaceutical industry with possibili-
critical advanced equipment, and highly skilled trained ties of improving drug delivery techniques with enhanced
human resources for the successful development and therapeutic outcomes and clinical benefits. Researchers are
approval from the regulatory bodies. These products face working across the globe to develop these types of products
obstacles right from the selection of API and excipients to for effectively mitigating various life-threatening diseases.
13
From the commercial success of various complex injecta- financial support. The author (Dr. Neelesh Kumar Mehra) would like
bles, it is very well understood that these drug products have to thank Department of Science and Technology (DST), Nanomission,
New Delhi, Government of India (Grant No. DST/NM/NS/2021/405),
the potential to improve the therapeutic outcomes along with for extending financial support.
significantly enhancing the patient compliance. Regulatory
bodies are putting efforts to promote more generic product Author contribution The idea for the article was created by Akash
competition and emphasizing excessively on collaborating Chaurasiya and Kanan Panchal. The literature search and data analysis
with the government, academia, and industry. In compari- were done by Akash Chaurasiya, Kanan Panchal, and Sumeet Katke.
The article was drafted by Kanan Panchal, Sumeet Katke, Sanat Kumar
son to the pharmaceutical industries, academic research Dash, Ankit Gaur, and Aishwarya Shinde. The article is critically
focuses more into the advanced drug delivery systems. In reviewed and revised by Akash Chaurasiya, Neelesh Kumar Mehra,
the future, such collaborative efforts by the regulatory bod- and Nithun Saha.
ies would help in translating the scientific knowledge from
the academia to the industries resulting in the fruition of the Funding This study was funded by Parenteral Drug Association, India
Chapter, and the Department of Science and Technology (DST), New
products from the pipeline. Along with the product devel- Delhi, Government of India.
opment, there is a requirement of rigorous research into the
field of analytical, structural, and physicochemical charac- Availability of data and materials Not applicable.
terization. Development of more reliable tools for charac-
terization would help in better understanding of the quality Declarations
attributes of the drug products, assisting the generic indus-
tries to match their drug product with the innovator. Further Ethics approval and consent to participate Not applicable.
research in the field of in silico PK modeling and experimen-
Consent for publication Not applicable.
tal in vitro-in vivo correlations is required which will help
the researchers to predict the in vivo product performance Competing interests The authors declare no competing interests.
resulting in designing more meaningful bioequivalence stud-
ies for the complex injectable formulations. Pharmaceutical
industries have recognized the value of designing the drug
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An Expanding Horizon of Complex Injectable Products: Development and Regulatory Considerations

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Drug Delivery and Translational Research (2023) 13:433–472

An expanding horizon of complex injectable products: development

Accepted: 3 August 2022 / Published online: 14 August 2022

Abbreviations I.V. Intravenous

Fig. 1 Classification of complex injectable products

Fig. 2 Historic turning points

Table 1 Challenges associated to complex injectables — Cause and Consequence

lauroxil ecule release 882 mg, monolaurate, 662 mg, Inc

polymeric compounds, naturally derived complex mixtures,

ment of enhanced containment [55]. Despite their synthetic

origin, specific drug molecules classified under non-biological

pounds) attribute intricacies with respect to structure, insuf-

lack of tools for physicochemical analysis [56]. Recombinant

of foreign DNA, produces human proteins in microorgan-

Prostate cancer, S.C.

to the complex nature of this product [59].

For the development and approval of complex API-based

generic products, it is mandatory to prove pharmaceutical

equivalence (inclusive of the API sameness) of the test

these complex APIs possess unique properties (like structure

conformities, particle size, and shape) which can only be

tools and techniques builds up the overall intricacy of the

Peptides and hormones

Peptides and hormones are generally used for numerous

therapeutic modalities such as the hormonal replacement

therapy wherein they add to or supplement if the endog-

Despite their benefits, the challenge lies in combating its

half-life and its successful incorporation into the human

body, as these are naturally occurring substances [61].

sis (MS via subcutaneous administration) [14]. Glatiramer

acetate is a mixture of synthetic polypeptides having unique

anti-inflammatory and immunomodulatory activities [62].

uct availability as a pre-filled syringe makes ­Copaxone® a

complex drug product. For better clarity and guidance of

generic product applicants, USFDA has published product-

specific guidance (PSG) for glatiramer. In this guidance, the

Antimicrobial peptides (AMPs) are oligopeptides used

Fig. 3 Multifaceted viewpoints

Fig. 4 Structure illustration of

Fig. 5 Frame work of PLGA

Polymeric particles indication of schizophrenia. Both ­Invega® Sustenna™ and

Device safety features Labeling requirement

Table 4 Characterization of Complex Injectable Products

1 Size and shape Dynamic light scattering Liposomes, nanoparticles, [126–132]

Small-angle X-ray scattering (SAXS) is a flexible and non-

Surface charge X-ray diffraction (XRD) is a non-destructive technique

Differential scanning calorimetry Lipid/polymer content analysis

Table 5 USFDA guidelines for injectable liposome preparation

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Abbreviations I.V. Intravenous

uct availability as a pre-filled syringe makes Copaxone® a

Polymeric particles indication of schizophrenia. Both Invega® Sustenna™ and