biologic drugs,,biosimilar and intended copy difference

1. Biosimilar and intended copies
(What the prescriber needs to know).
BY
Mohie-Aldien A Sherif
Professor of Pharmacology, Faculty of Medicine, Benha University,
Benha, Egypt

2. Properties Small molecules
Drugs
Biological Drugs
(protein/Abs/ Vaccines /ASO /
miRNA)
Non Biological Drugs
(using nano-particle)
manufacture Chemical synthesis Produced in living cells e.g. nano-medicines.
mol. wt. < 200-500 Da wt. 7-> 100 kDa . > 900 kDa;
structure Simple –well defined Complex, heterogeneous defined by manufacture processes.
Stability Stable Unstable, sensitive to external conditions
Copying Yes (Produces by one batch;
Contamination can be detected
Easy to purify).
Difficult to insure identical copy version due to complex
technology
immunogenicity low high varies
targets Proteins at membrane /
intracellular
Proteins at membrane /
intracellular /RNA or DNA
Proteins /RNA or DNA
intracellular
ADME/
PK properties
Orally bio-available; Not orally bio-available; given parenteraly
distributed to all organs and
tissues, cell permeable;
distributed mainly in plasma or
extracellular fluids, cell impermeable;
distributed to all organs and
tissues, cell permeable;
excreted mainly in bile/ urine limited excretion limited excretion
metabolized (inorganic not)
→ interactions
Protein (catabolized to peptides or AA);
nucleotides catabolized by nucleases.
complex
Types of DRUGS

3. Indian J Med Res. 2020 Nov; 152(5): 456–467

5. Cancer Medicine, Volume: 3, Issue: 4, Pages: 889-899, First published: 09 May 2014, DOI: (10.1002/cam4.258)
The manufacturing process to produce biologics and similar biologics, include
complex and controlled procedures may lead to heterogenicity

8. Analytical Analytical
ORIGINAL BIOLOGIC BIOSIMILAR
Objective:
Demonstration of
clinical efficacy
Objectives:
1- Demonstration of clinical efficacy.
2- Demonstration of Highly similarity and no clinically
meaningful differences in safety, purity and potency in
one or more appropriate conditions of use for which the
reference product licensed
Preclinical
Preclinical
Clinical Pharmacology
Clinical Pharmacology
Clinical Studies
Clinical
Studies
Post-marketing plan is essential for approval

11. EMA [11] WHO [10] Canada [45] USA [12, 76] Japan [60] Australia [90]
Definition
A biologic medicinal product
similar to another biologic
medicine that has already
been authorized for use
A biotherapeutic
product that is similar in
terms of quality, safety,
and efficacy to an
already licensed
reference
biotherapeutic product
A biologic drug that
enters the market
subsequent to a version
previously authorized in
Canada, with
demonstrated similarity
to a reference product
A biologic product highly
similar to the reference
product notwithstanding
minor differences in
clinically inactive
components
A biotechnological
drug product
developed by a
different company,
which is
comparable with
an approved
biotechnology-
derived product
A version of an already
registered biologic medicine
that has a demonstrable
similarity in physicochemical,
biologic, and immunological
characteristics, efficacy, and
safety, based on
comprehensive comparability
studies
Preclinical
data
Target binding; signal
transduction, functional
activity/viability of cells of
relevance. If in vitro
comparability is satisfactory,
animal studies may not be
required
Receptor-binding or cell-
based assays; relevant
biologic/PD activity,
toxicity
Receptor-binding or cell-
based assays; Animal PD
and repeat-dose toxicity
studies, and other
relevant safety
observations
Structural analyses,
functional assays; animal
toxicity assessments,
PK/PD, immunogenicity
(unless determined not
necessary by FDA)
Toxicity and
pharmacologic
assessments, PK,
and local tolerance
Similar to EMA
Clinical
trials
Comparability demonstrated
in stepwise process using PK,
PD (if feasible), followed by
clinical efficacy and safety
trials
PK, PD, (confirmatory
PK/PD), efficacy, and
safety
PK, PD, clinical efficacy,
and safety, including
immunogenicity
Study or studies
including assessments of
immunogenicity and PK
or PD
PK, PD (with
appropriate PD
marker) consider
safety studies
(immunogenicity)
Similar to EMA
Naming
Commercial name,
appearance, and packaging
should differ; INN should be
the same for related
biosimilars
Changes are being
considered to the
current policy of using
INN
Not specified
Draft guidance proposes
that all biologics be
given a four-letter suffix
to the INN
Non-proprietary
name of the
reference product
followed by “BS”
and an
abbreviation to
reference the
manufacturer
Australian biologic name
without a specific biosimilar
identifier suffix (policy is
under review)
Pharmacovi
gilance
Risk management
pharmacovigilance plan
must be submitted; clinical
safety monitored closely
after marketing
authorization
Pharmacovigilance plan
submitted with
marketing authorization
application; describe
planned post-marketing
activities
Risk management plan
submitted prior to
marketing authorization;
periodic safety update
reports. Serious adverse
drug reactions reported
within 15 days
Any risk evaluation and
mitigation strategy for
the reference product
applies. Post-marketing
studies or additional
clinical trials could be
mandated
Post-authorization
safety studies
monitored on a
continuous basis
Risk management plan
outlining pharmacovigilance
procedures to be
implemented submitted with
biosimilar application
Overview of biosimilar regulatory guidelines

12. Classification of biopharmaceutical agents.
Indian J Med Res. 2020 Nov; 152(5): 456–467.

13. Intended copy/ Biomimcs/ Biocopies /
Non comparable biologic
Biosimilars
Biological originator
Biological products that show
BUT
similarity with Original
did not followed by rigorous
regulatory approval system consistent
with WHO/ EMA/FDA guidelines 1,2
approved by rigorous regulatory
approval system consistent with WHO/
EMA/FDA guidelines (Abbreviated
biologics license application) and based
on demonstration of similarity in
Physicochemical properties; structural
properties; functional properties;
Immunochemical properties; Purity and
impurity profiles; stability and
degradation profiles1,2,3.
biologics license
application) for
particular indications
by regulatory
authority by rigorous
regulatory approval
system consistent
with WHO/
EMA/FDA
guidelines1,2
Definition
Higher heterogeneity 3
Not establish comparability with
the original product.4,5
 Micro-heterogeneous product 3
 Little variation and were consistently
within the rigorous specifications
defined by regulatory agencies
compared to original 4, 5, 6.
Micro-Heterogeneous
product3
Product
heterogeneity

14. Product Market Authorization Holder Country Status
Yisaipu
Shanghai CP Guojian
Pharmaceutical Co, Ltd
China
Marketed as a recombinant human tumor necrosis
factor-α receptor II – IgG Fc fusion protein.18
Etanar®
Lafrancol (Laboratorio Franco-
Colombiano SA)
Colombia Described as a new biologic type rhTNFR:Fc.19
Etacept Cipla India Marketed as a biosimilar of etanercept.20
Infinitam Probiomed Mexico Marketed as a biosimilar of Enbrel.21
Altebrel™ Aryogen Iran Marketed as a biosimilar for etanercept.22
Intacept Intas India Marketed as a biosimilar for etanercept.23
Qiangke Shanghai Celgen Biopharma China Marketed as a new biologic.24
Origin and status of IC products assessed
Variability of intended copies for etanercept (Enbrel®):
Data on multiple batches of seven products
MAbs. 2018 Jan; 10(1): 166–176. Published online 2017 Nov 7. doi: 10.1080/19420862.2017.1387346

15. In conclusion,
•None of the batches for the ICs tested (n = 24) met the criteria
that would be typically applied to establish comparability with
the innovator product.
•The combination of the results from these analyses and the
limited clinical data available indicate that Yisaipu, Etanar®,
Etacept, Infinitam, Altebrel™, Qiangke, and Intacept should not be
considered biosimilar to etanercept as per the standards outlined
in WHO, FDA, or EMA guidance.
Variability of intended copies for etanercept (Enbrel®):
Data on multiple batches of seven products
MAbs. 2018 Jan; 10(1): 166–176. Published online 2017 Nov 7. doi: 10.1080/19420862.2017.1387346

16. The apparent absence of comparative clinical data at the time of
marketing authorization of rituximab product RTXM83 led other
authors, in a 2016 publication, to conclude that the product could
not be considered a true biosimilar.
Generics Biosimilars Initiat J. 2016;5(2):66–69. doi:10.5639/gabij.2016.0502.017.
Tout et al,, highlighted that a PK analysis of the rituximab product
Reditux™ yielded markedly different results than those reported
separately for originator rituximab.
Cancer Chemother Pharmacol. 2016; 78(6):1317–1318. doi:10.1007/s00280-016-3176-6.
Scheinberg noted that the efficacy results in an observational
study of the etanercept product Etanar® were significantly
different from those reported previously in the literature for the
originator product.
Scheinberg M. Is Etanar a new biologic? Clin Exp Rheumatol. 2016;34(5):954.

17. Intended copy
Biosimilar
Biological
original
NO / Non comparable
well designed studies to
show Similarity to
structure to original in
identity, purity and
potency , Not published
5,13,14,20
A comprehensive comparability Vs
original show at least Non-inferiority:
 Protein content: 1.5 -SD of original.
 Physical properties: 3 SD of original.
 Bioassay limits: (potency): 80–125 % of
the stated potency.
 equivalence criteria 1.5 × SD of
original to define the 90% confidence
limit
 Post-translation modifications,
aggregates: within 3 × SD of original.
 Impurities: must not have any
unmatched impurity. 5,15,16,17,18,19,20
concern the
manufacturi
ng process
changes
and clinical
trials
5,14,15,16
Analytical
Studies

18. Nonclinical in vivo studies are conducted after analytical
characterization of the biosimilar, and are designed to address any
specific residual analytical uncertainty and, in some jurisdictions, ensure
safe use in humans.
Although global guidelines on biosimilar development are largely
aligned in terms of the analytical and clinical aspects, there is substantial
variability in the amount and type of in vivo nonclinical data required,
with the EMA guidelines recommending minimal to no use of in vivo
assays (EMA, 2015) whereas other countries, such as Japan and China,
require more extensive toxicity studies
Kirchhoff et al; .Biotechnol Bioeng; 2017Dec;114(12):2696-2705

19. Intended copy
Biosimilar
Biological original
NO /or
Observational,
non comparative
trials (mostly
not published) Vs
original5.18,17,18,19,
20,21,22
compares the profile (80–125% bioequivalence)
-Smaller sample number.
- can combine antidrug Abs measurements in a parallel
design
• Single dose, comparative5,15,16,17,18,19,20
Larger no of volunteers
to cover the variability
(gender, age, and genetic
diversity) .Single
dose/Repeat dose5,14,15,16
PK/PD /
Immu-
Noge-
nicity
Clinical
studies
Toxicology
Repeat dose 5,14,15,1617,18,19
Toxicology: Single/
Repeat dose; Geno-
toxicity/ carcino-genicity;
Reproduction; Local
tolerance 5,14,15,16

20. Intended copy
Biosimilar
Biological original
NO /or
Observational,
non
comparative
trials (mostly
not published)
Vs
original5.18,17,18
,19,20,21,22
- RC(Vs original )T powered to show non-inferiority Vs
original.
- Determined according to the outcome of the quality of
preclinical results. (More differences → more clinical and
non-clinical studies should be done vs original ..
- More sensitive endpoints to detect the impact of the
minimal variation between a biosimilar and its original on
the patients (more sensitive biomarkers are needed) and
risk/benefit ratio.
- More safety / immunogenicity studies.
-Published in well known periodicals.
- Registered of the a protocol in clinicaltrials.gov.
- Announcements in global biosimilar news websites. 5,11,
14,15,1617,18,19
- Randomized Double
Blind (RCT)
demonstrate Non-
inferiority efficacy
and safety against an
existing therapy or
placebo
- The Endpoints are
standard and known
(Long-term
risk/benefit outcomes )
5,14,15,16
Efficacy
/risk
Clinical
studies
essential for approval
essential for approval
PM Plan

21. July 2018;Journal of Clinical Rheumatology: Practical Reports on Rheumatic & Musculoskeletal Diseases 25(2):1
DOI:10.1097/RHU.0000000000000881
Biosimilars and Intended Copies Available in Latin America in 2018 for the Treatment
of Rheumatic Diseases

22. In summary, most comparative studies reported for intended
copies were either analytical/nonclinical or observational in
nature, with only a single RCT identified for Infinitam .
Suffice to say, significant evidence gaps remain with respect to
the efficacy and safety of intended copies for the treatment of
cancer and chronic inflammatory diseases based on the
published information currently available.
November 2016,BioDrugs 30(6), DOI:10.1007/s40259-016-0199-9

23. Intended copy
Biosimilar
Biological
original
Different , put patient safety at risk to
develop side effect 2,5, 11,12,13,14
Similar 2;6,7,8,9,10
Not Applicable (NA)
Quality , safety and efficacy
compared to the original
the data available to assess intended copies do not provide adequate comparable
efficacy and safety to the licensed product. These products may have clinically
significant differences in formulation, dosages, efficacy, or safety from what is
required for a biosimilar (Mysler, et al ; Rheumatol Int. 2016 May;36(5):613-25
A significant percent (14.3%) of patients receiving Infinitam/Etanar or
Kikuzubam, intended copies of etanercept and rituximab, respectively,
experience Grade 3/4 AEs with a very short time to onset. ABSTRACT NUMBER: 1506,
Meeting: Dörner T. et al. Ann Rheum Dis2013;72:322.
•It is important for physicians to know the difference among biologic, biosimilar,
bio-better and an 'intended copy' to make an informed decision before prescribing
them for therapy or substitution for a reference product.
•the ideal medical ethic of 'do no harm' must be followed.
•intended copies put patient safety at risk.
apollo medicine 12 (2015) 103–111

24. Intended copy/ Biomimcs/ Biocopies /
Non comparable biologic
Biosimilars
Biological
originator
‫؟‬
8-10 y
23
15 y
23
Development
time
No23
No
23
Yes (12) years
23
patent
licensing
NA (did not followed by rigorous regulatory
approval system consistent with WHO/
EMA/FDA guidelines) 1,2
Case by case bases
23
NA
23
Indication
extrapolation
‫؟‬
100-250 Millions $
2 Billions $
Cost
Are available in countries with relaxed
regulations e.g. China, Colombia and
India 24,25.
Are available in highly
regulated markets such
as US, Europe and
Australia
23,24
Are available in
highly regulated
markets e.g US,
Europe and
Australia
23,24
Availability

25. Highly regulated markets ensure
safe biosimilar medicines
• Biosimilar quality is assured by rigorous testing requirements, which
include head-to-head analytical/non-clinical/clinical testing against
the reference originator. In addition, the regulatory authorities, such
as the European Medicines Agency (EMA) and US FDA, require
robustness in manufacturing process
• To date, there have been no reports of a biosimilar medicine in
highly regulated markets being associated with any unusual or
unexpected adverse events as compared to its originator
• In Europe, no unusual or unexpected clinical events have been
observed with biosimilars of somatropin, epoetin, or filgrastim
• In the USA, no unusual or unexpected adverse events have been seen
with products approved as follow-on biologics on the basis of
abbreviated data packages, including Omnitrope®
McCamish M and Woollett G. The state of the art in the development of biosimilars. Clin Pharmacol Ther 2012;91(3):405–417.

26. Biosimilars
Biological originator
Not Applicable ( not
followed by rigorous
regulatory approval system
consistent with WHO/ EMA/
FDA guidelines) 1,2
Case by case bases 23 OR Clinical studies of equivalence in the most
sensitive indication is needed 23,32,33
Indication
extrapolation
●FDA’s position that interchangeability requires a higher evidence
standard than biosimilarity, Label should clearly indicate whether a
biologic is interchangeable with the reference product for
autosubstitution.34
●EMA (variability in between countries regulation but mainly Auto-
substitution is permitted35
●Australia and Canada: Auto-substitution is permitted35
●Japan and Brazil: Physician directed switching35
●Switching between biosimilars has not been evaluated in
randomized controlled trials35
Switching
(physician decision)
Vs
Automatic
Substitution or
inter-changeability
(pharmacist
decision) between
original and
biosimilar

27. it is important for both regulators and physicians to be
aware fully of the differences between legitimate
biosimilar medicines and intended copies.
Biosimilars in rheumatology: recommendations for
regulation and use in Middle Eastern countries
Clinical Rheumatology volume 37, pages1143–1152 (2018)
•The increasing availability of biosimilar medicines in Middle Eastern
regions may provide an opportunity to increase the number of
rheumatology patients who have access to traditionally more expensive
biologic medicines BUT ; The problems are:
1- The lack of real world data on the use of biosimilar medicines in
practice.
2- the availability of intended copies in the region may undermine
physician confidence in prescribing legitimate biosimilar medicines.
•
Nizar Al Ani
,
Bassel El Zorkany
,
‫ك‬
Hani Al Moallim
&
Mohamed Mounir
,
Yasser El Dershaby
,
mad Uthman
,
Jamal Al Saleh
,
Samar Al Emadi

28. The nocebo effect (the opposite to the placebo Effect) is the opposite to
the placebo effect, being defined as ‘‘a negative effect of a pharmacological or
non-pharmacological medical treatment that is induced by patients’
expectations, and that is unrelated to the physiological action of the
treatment’. The nocebo effect may come into play when patients are switched
from a reference biologica to a biosimilar.
The nocebo effect is presented by Increased symptom burden, psychological
distress, and the number of adverse events experienced by patients; non-
adherence, reduced quality of life, and wasted medication; increased
healthcare costs; more complicated treatment regimens; and the cost savings
from biosimilars not being realized.
However, a large systematic review of double-blind versus open-label studies
of switching from an originator product to a biosimilar across several
therapeutic areas noted that current evidence is insufficient to confirm a
biosimilar nocebo effect, although there was some evidence to support the
theory [125].
March 2022;Ophthalmology and Therapy 11(3);DOI:10.1007/s40123-022-00488-w

29. intended copy

30. Products previously approved as intended copy
biologic drugs should be evaluated according
to the current regulations specific to those
required for biosimilars and within a specified
time period or be removed from market.
Rheumatol Int (2016) 36:613–625

31. In Mexico, for example, there were 23 intended
copies, or “biolimbos,” on the market before the
country’s biosimilar guidelines came into effect,
and the regulator COFEPRIS has requested that the
manufacturers conduct assessments to
demonstrate the biosimilarity of these agents and
the corresponding originator products.
GaBI Online. Mexico issues rules on biolimbos. 2015 Mar 13 [accessed 2017 Apr 6].
http://www.gabionline.net/Guidelines/Mexico-issues-rules-on-biolimbos. [Google Scholar]

32. Recent legislation has stipulated that these intended
copies should be subject to the same regulations as
biosimilars and a complete assessment of these
products is expected to take 2 years from the effective
date of the new regulations . However, re-evaluating
intended copies that were previously approved and
now do not fit within each country’s.
Future Oncol. (2021) 17(19), 2529-2544

33. OMATROPIN (SEDICO):26,27,28
- NO published comparative (Vs original) analytical or clinical trials in approved indications
(e.g.Pubmed,Google)
- Only 3 Non comparative (Vs original) with insufficient power, for off-lable indications and
published in a conference or national J with negative results.
Example of Intended copy
GENELEUKIM (CSPC)29:
- Origin: China
- No comparative (Vs original) analytical or clinical published data (e.g. Pub med. Google or
clinical trial.gov , not mentioned in Wikipedia as a.biosimilar
RITUXIGEN: 30.,31
-Not reported as biosimilar until 2022.30.,31
-No Data in google, pubmed, or clinical trial.gov , not mentioned in Wikipedia as a.biosimilar
Kikuzubam25:gaining approval without published comparative clinical studies to provide
evidence of its safety or efficacy, it was withdrawn from the market by the regulatory authority,
owing to the documented anaphylactic reactions and lack of clinical data:
Reditux25: has been marketed in Latin American markets, India, and Iran, without rigorous data
to indicate structural or functional similarity or clinical effectiveness compared with rituximab.
Reditux TM shows heterogeneity with respect to structure, and RCTs are lacking.

34. Intended copies:
•Are not good.
•Are not bad .
BUT;
•THEY ARE UNKNOWN.

35. References
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Nov/Dec;9(8):1337-1348..
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•Mysler E, Pineda C, Horiuchi T, et al. Clinical and regulatory perspectives on biosimilar therapies and intended copies of biologics in rheumatology. Rheumatol Int. 2016 May;36(5):613-25.
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Mexico. Arthritis Rheumatol. 2014;66(Suppl 10):1506
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as active substance: non-clinical and clinical issues. European Medicines Agency. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2015/01/WC500180219.pdf.
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• Azevedo V.F., Babini A, Carlo V. Caballero-Uribe, et al Practical Guidance on Biosimilars, With a Focus on Latin America What Do Rheumatologists Need to Know? J Clin Rheumatol. 2019
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36. THANK you

37. Category Quality attribute Methods
Physicochemical characterization
Primary structure Amino acid sequence Red. RP-HPLC–ESI–MS peptide mapping,
intact mass of whole mAb, HC and LC by
RP-HPLC–ESI–MS, Red. RP-HPLC-UV
peptide mapping
Higher order structure Disulfide bridging Free thiols Secondary and
quaternary structure Thermodynamic stability
Non-red. RP-HPLC-ESI–MS peptide
mapping Ellman's assay CD, FTIR, HDX-
MS, X-ray DSC
General charge
heterogeneity and amino
acid modifications
0 K variant, acidic variants, basic variants, Gln-variant,
Lys-variant, amidated proline Glycation
Oxidation/deamidation/C-terminal variants
CEX digested/undigested Boronate
affinity RP-HPLC-UV/MS peptide
mapping
Glycosylation Galactosylation, sialylation, mannosylation,
afucosylation, bisecting GlcNAc, NGNA, α-galactose,
qualitative glycosylation pattern
NP-HPLC-FL
Size heterogeneity Monomer, low molecular weight (LMW) and high
molecular weight (HMW) variants (aggregates) Heavy
chain (HC), light chain (LC), aglycosylated HC, clipped
variants Monomer, LMW (e.g., half antibodies and
HHL variant) and HMW variants Subvisible particles
Visible particles
SEC, AF4 Red. CE-SDS Non-red. CE-SDS
Light obscuration (PhEur, ≥10 μm and
>25 μm) Visual inspection (PhEur)
Functional characterization
Target and receptor
binding
FCRn binding SPR FcγR binding (FcγRIa, FcγRIIa,
FcγRIIb, FcγRIIIa(F158), FcγRIIIa(V158), FcγRIIIb) SPR
Bioactivity CD20 target binding CDC potency ADCC potency
Apoptosis
Cell-based binding assay Cell-based CDC
assay Cell-based ADCC assay Cell-based
apoptosis assay
An overview of the characterization of mAb biosimilar (Visser, etal,2013)