This document summarizes a presentation on biological medicines and monoclonal antibody therapeutics. It discusses regulatory guidelines for biosimilars in Korea and ASEAN countries. The presentation provided an overview of global biosimilar guidelines, noting that the EU implemented the world's first well-organized biosimilar legislation and guidelines. It also noted that Korea has issued biosimilar guidelines since 2009, and Malaysia and Singapore are leading implementation of biosimilar guidelines in ASEAN countries.
4. Recombinant Therapeutic Mabs approved or in review in the EU and US (as of 2-28-2013)
International nonproprietary name
Muromonab-CD3
Abciximab
Rituximab
Basiliximab
Daclizumab
Palivizumab
Infliximab
Trastuzumab
Gemtuzumab ozogamicin
Type
Anti-CD3; Murine IgG2a
Anti-GPIIb/IIIa; Chimeric IgG1 Fab
Anti-CD20; Chimeric IgG1
Anti-IL2R; Chimeric IgG1
Anti-IL2R; Humanized IgG1
Anti-RSV; Humanized IgG1
Anti-TNF; Chimeric IgG1
Anti-HER2; Humanized IgG1
Anti-CD33; Humanized IgG4
Indication first approved
Reversal of kidney transplant rejection
Prevention of blood clots in angioplasty
Non-Hodgkin's lymphoma
Prevention of kidney transplant rejection
Prevention of kidney transplant rejection
Prevention of respiratory syncytial virus infection
Crohn disease
Breast cancer
Acute myeloid leukemia
First EU (US) approval year
1986* (1986#)
1995* (1994)
1998 (1997)
1998 (1998)
1999 (1997); #
1999 (1998)
1999 (1998)
2000 (1998)
NA (2000#)
Alemtuzumab
Adalimumab
Tositumomab-I131
Efalizumab
Cetuximab
Ibritumomab tiuxetan
Omalizumab
Bevacizumab
Natalizumab
Trade name
Orthoclone Okt3
Reopro
MabThera, Rituxan
Simulect
Zenapax
Synagis
Remicade
Herceptin
Mylotarg
MabCampath, Campath1H
Humira
Bexxar
Raptiva
Erbitux
Zevalin
Xolair
Avastin
Tysabri
Anti-CD52; Humanized IgG1
Anti-TNF; Human IgG1
Anti-CD20; Murine IgG2a
Anti-CD11a; Humanized IgG1
Anti-EGFR; Chimeric IgG1
Anti-CD20; Murine IgG1
Anti-IgE; Humanized IgG1
Anti-VEGF; Humanized IgG1
Anti-a4 integrin; Humanized IgG4
Chronic myeloid leukemia
Rheumatoid arthritis
Non-Hodgkin lymphoma
Psoriasis
Colorectal cancer
Non-Hodgkin's lymphoma
Asthma
Colorectal cancer
Multiple sclerosis
2001 (2001)
2003 (2002)
NA (2003)
2004 (2003); #
2004 (2004)
2004 (2002)
2005 (2003)
2005 (2004)
2006 (2004)
Ranibizumab
Panitumumab
Eculizumab
Lucentis
Vectibix
Soliris
Anti-VEGF; Humanized IgG1 Fab
Anti-EGFR; Human IgG2
Anti-C5; Humanized IgG2/4
Macular degeneration
Colorectal cancer
Paroxysmal nocturnal hemoglobinuria
2007 (2006)
2007 (2006)
2007 (2007)
Certolizumab pegol
Golimumab
Canakinumab
Cimzia
Simponi
Ilaris
Crohn disease
2009 (2008)
Rheumatoid and psoriatic arthritis, ankylosing spondylitis 2009 (2009)
Muckle-Wells syndrome
2009 (2009)
Catumaxomab
Ustekinumab
Tocilizumab
Ofatumumab
Denosumab
Belimumab
Ipilimumab
Removab
Stelara
RoActemra, Actemra
Arzerra
Prolia
Benlysta
Yervoy
Brentuximab vedotin
Pertuzumab
Adcetris
Perjeta
Anti-TNF; Humanized Fab, pegylated
Anti-TNF; Human IgG1
Anti-IL1b; Human IgG1
Anti-EPCAM/CD3;Rat/mouse bispecific
Mab
Anti-IL12/23; Human IgG1
Anti-IL6R; Humanized IgG1
Anti-CD20; Human IgG1
Anti-RANK-L; Human IgG2
Anti-BLyS; Human IgG1
Anti-CTLA-4; Human IgG1
Anti-CD30; Chimeric IgG1;
immunoconjugate
Anti-HER2; humanized IgG1
Raxibacumab
(Pending)
Trastuzumab emtansine
Kadcyla
Vedolizumab
(Pending)
Anti-B. anthrasis PA; Human IgG1
Anti-HER2; humanized IgG1;
immunoconjugate
Anti-alpha4beta7 integrin; humanized
IgG1
Source: Janice M. Reichert, Editor-in-Chief, Mabs
Malignant ascites
Psoriasis
Rheumatoid arthritis
Chronic lymphocytic leukemia
Bone Loss
Systemic lupus erythematosus
Metastatic melanoma
2009 (NA)
2009 (2009)
2009 (2010)
2010 (2009)
2010 (2010)
2011 (2011)
2011 (2011)
Hodgkin lymphoma
Breast Cancer
2012 (2011)
2013 (2012)
Anthrax infection
NA (2012)
Breast cancer
2013
Ulcerative colitis, Crohn disease
In review (NA)
5. Mabs ranked in the Top Ten Drugs in 2012
•
•
•
•
•
•
•
•
•
•
Humira (AbbVie)
- Mab
Advair (Glaxo Smith Kline)
Rituxan (Roche)
- Mab
Lantus (Sanofi)
Herceptin (Roche)
- Mab
Crestor (AstraZeneca)
Remicade (Johnson & Johnson)
- Mab
Avastin (Roche)
- Mab
Cymbalta (Eli Lilly and Co)
Plavix (Sanofi & Bristol-Myers Squibb)
6. Developing Standards for Mabs
Challenges in developing Mab standards
• Structure is complex, often heterogeneous, with a mix of isoforms,
glycoforms etc.
• Need to understand the importance of each form
• Many types of impurities, requiring different types of analytical
methods. Impurities often are manufacturing process-dependent
• Potency assay (Bioassay) is a key quality attribute. Multiple potency
assays are needed to address different functional domains
7. IgG Structure and Functional Domains
Variable
Region
CH1
VL
CL
Constant
Region
CH2
Fc
• Effector Functions
ADCC (FcgRI, II, III)
CDC (C1q)
• FcRn binding
CH3
Multiple domains lead to multiple variants requiring a battery
of physicochemical and biological tests
13. ADCC Activity
Antibody Dependent Cell-Mediated Cytotoxicity
Target B-Cell
Cytotoxic
mediators
Dead B-Cell
upon ADCC
Rituximab
Effector Cell
Fc Receptor RI, RIII
14. Potency Assays for Rituximab
CDC assay
Cell line: WIL-2S
Cell viability measured by AlamarBlue
Readout: fluorescence
ADCC assay
Target cells:
WIL2-S
Effector cells: Jurkat cell engineered
to express FcgRIII and NFAT-luciferase
reporter gene;
Readout: luminescence
15. CDC-Based Potency Assay for Rituximab
Acceptable Procedure
USP Reference Procedure
Cell line and bioassay: CDC assay using CD20+
cells
CDC assay using WIL-2S cells, human
complement and Resazurin-based
detection reagent
Data Analysis: Relative potency (RP) calculated
according to appropriate data analysis guidelines
Relative potency calculated per USP
<1034> and validated per USP <1033>
Specificity: Unrelated Mab and Formulation buffer
should not show activity.
Unrelated Mab and Formulation buffer
showed no activity.
Precision (Repeatability): RSD ≤ 10%
RSD 5%
Precision (Intermediate precision): RSD ≤ 15%
RSD 9%
Linearity: r2 > 0.9 measured and expected
potency
r2 1.0
Accuracy: Spike recovery 85%–115%
Range: Minimally cover 80%-125%; wider is better
95%–105%
64% to 156%
19. Role of Fc Glycans in Mab Functions
Terminal galactose is important for CDC
N-Acetyl glucosamine essential for ADCC
Bisecting N-Acetyl glucosamine enhances ADCC
Core fucose inhibitory to ADCC; afucosylated variants show higher ADCC
High-mannose glycans reduce half life of IgG
120
Degalactosylation
abolishes 40% of
CDC activity.
% Potency by CDC assay
•
•
•
•
•
100
80
60
40
20
0
Treatment with Beta-Galactosidase
20. Glycan Profiling of Mabs
Deglycosylation with PNGase followed by 2-Aminobenzamide labeling and Normal
Phase UPLC. Peaks are characterized using 2AB-Labeled glycan standards
2.50
G1F’
G1F
G0F
3.00
c
c
2.00
G0
N-acetyl glucosamine
G2F
Core Fucose
Galactose
Sialic Acid
G2FS1
G2
G1’
G1
Man 5
0.50
G0F-GN
1.00
G2FS2
1.50
G0-GN
EU
Mannose
0.00
6.00
8.00
10.00
12.00
14.00
16.00
18.00
Minutes
20.00
22.00
24.00
26.00
28.00
30.0
21. N- & C-terminal Charge Variants of Mabs
E
E E pE
pE
pE pE
pE
E pE
VH
CH1
VL
CL
CH2
S
L
S
L
S
P
G
K
S
L
S
L
S
P
G
K
Un-Processed
SS
L L
SS
L L
SS
PP
GG
K
Partially Processed
S S
L L
S S
L L
S S
PP
GG
K
CH3
Partially Processed
E = N-terminal glutamate; pE = N-terminal pyroglutamate; K= C-terminal lysine
Other charge variants: Deamidation, glycation, terminal sialic acid
S
L
S
L
S
P
G
S
L
S
L
S
P
G
Fully Processed
28. CONTENTS
SECTION I.
SECTION II.
Overview On Global Biosimilar Guidelines
KOREA & ASEAN Regulatory Environments
SECTION III. Biosimilar Guidelines in KOREA
SECTION IV. Biosimilar Guidelines in ASEAN
SECTION V. Executive Summary
30. Global Regulation or Guideline on Biosimilar
[SUMMARY]
EU: In fact, world first well-organized biosimilar legislation and guideline were implemented in EU.
KOREA: Biosimilar guidelines have been issued since first biosimilar guideline was implemented in 2009.
ASEAN: Malaysia and Singapore are leading implementation of biosimilar guidelines in ASEAN.
2011
SNG
2012
2013
USA
EGY
India
31. Global Regulation or Guideline on Biosimilar
[SUMMARY]
Biosimilar Pathway: EU, Brazil, Argentina,Turkey, Malaysia, Canada, Mexico, Korea, Japan, India,
Singapore, Egypt, Saudi Arabia, Australia, US, Venezuela
Biosimilar Pathway under Development: Peru, Chile, Ecuador, Colombia, Bolivia, Paraguay, Uruguay,
Pakistan, South Africa, New Zealand, Philippines, Hong Kong, Vietnam, Indonesia, Thailand
Biosimilar Pathways
Biosimilar Pathways
under Development
No Biosimilar Pathway
33. Guideline on Biosimilar in KOREA & ASEAN
[SUMMARY]
Korea, Singapore and Malaysia has their own biosimilar pathway.
Other ASEAN countries does not have official biosimilar pathway yet.
CLASSIFICATION
COUNTRY
Biosimilar Pathways
(1+2)
Biosimilar Pathways
under Development
(4)
Biosimilar Pathways
under Development
No Biosimilar Pathway
Philippines, Vietnam,
Indonesia, Thailand
No Biosimilar Pathway
(4)
Biosimilar Pathways
Korea, Malaysia,
Singapore
Laos, Myanmar,
Cambodia, Brunei
Darussalam
34. Regulatory Environment in Korea & ASEAN
[SUMMARY]
Regulatory Agency in Indonesia and Thailand has tendency to treat biosimilar filing as new biologics
with less requirements
Regulatory Agency in Indonesia and Thailand has tendency to treat biosimilar filing as generic pathway
with more requirements
Regulatory Environment
COUNTRY
Biosimilar Pathway
Korea, Malaysia, Singapore
New biologics (with less
requirement)
Indonesia, Thailand
Generic Pathway
Philippines, Vietnam
Unknown
Laos, Myanmar, Cambodia,
Brunei Darussalam
35. Regulatory Environment in Korea & ASEAN
[SUMMARY]
KOREA: Regulatory Agency is being changed with its name and function.
Philippines: Regulatory Agency is being changed with new PFDA commissioner.
Thailand and Malaysia: GMP Inspection or Accreditation is time-consuming.
COUNTRY
Regulatory Environment
Korea
Name and organization of Korea FDA was
changed in March 2013.
Name: KFDA MDFS (Ministry of Drug and
Food Safety)
Organization and Function: Being changed
to extend its function.
Singapore
EU or US CPP is required.
Malaysia
Long waiting list for GMP Inspection.
Thailand
TFDA is now preparing biosimilar guideline
GMP Accreditation Process was implemented.
Philippines
Organization of PFDA is being changed with
new commissioner.
Indonesia
Local Manufacturing is required.
Vietnam
Special Quota VISA & Valid VISA are available.
Laos, Myanmar,
Cambodia, Brunei
Darussalam
Not known.
38. Guideline on Biosimilar in KOREA
[SUMMARY]
KOREA has similar structure with EU biosimilar guideline
Legislation: Regulations on Review & Authorization of Biological Products (KFDA Notification No. 2009-59)
Guideline: 8 relevant guidelines and 1 Q&A are now available.
Definition/Principle
General Guidelines
Quality, Safety,
Efficacy
Product Specific
Requirement
39. Guideline on Biosimilar in KOREA
Overarching Guideline
Guidelines on the Evaluation of Biosimilar Products (2009)
SCOPE
In principle: Biosimilar concept applicable to any biological medicinal product.
In practice: Only for products that can be thoroughly characterised.
[Choice of Reference Product]
Korea
The reference product should be
authorized in Korea. However, if the
registered reference product is not
available in Korea commercially, the same
biological product as the one authorized in
Korea (including the manufacturing site
and the manufacturing process) may be
purchased from overseas markets and
used as the reference product.
EU (Reference Information)
Must be authorised in the EU based on a
complete dossier.
40. Guideline on Biosimilar in KOREA
Overarching Guideline
Guidelines on the Evaluation of Biosimilar Products (2009)
[Quality Requirement]
Korea
A complete description of the
manufacturing process for the drug
substance and drug product should be
provided in detail including information on
quality control/quality assurance, inprocess controls, and process validation.
Comparability study along with
specifications, analytical procedures
and stability study should be
conducted.
EU (Reference Information)
For recombinant proteins, an extensive
comparability exercise is required.
Quality aspects of comparability must be
considered in relation to implications for
safety and efficacy. Purity and impurity
profiles of the active substance and
medicinal product must be assessed
qualitatively and quantitatively for the
biosimilar and the reference product.
41. Guideline on Biosimilar in KOREA
Overarching Guideline
Guidelines on the Evaluation of Biosimilar Products (2009)
[Nonclinical Data]
Korea
EU (Reference Information)
▶
„ In vitro studies:
Assays, such as receptor-binding studies or cellbased assays should normally be undertaken in
order to establish the comparability of the
biological/ pharmacodynamic activity of the
biosimilar product and the reference product, should
be conducted
Non-clinical studies for biosimilar versions
of recombinant proteins should be
comparative in nature, designed to
detect differences in response between the
biosimilar and the reference product.
In vitro studies, in vivo studies in
relevant animal species, and at least
one repeat-dose toxicity study in
relevant animal species normally should be
conducted.
▶
„ In vivo studies:
- Animal studies should be performed in species know
to be relevant
- At least one repeat-dose toxicity study
- Other toxicological studies, including safety
pharmacology, reproductive toxicology, mutagenicity
and carcinogenicity studies are not required for
biosimilar unless warranted by the results from
repeated toxicological studies.
42. Guideline on Biosimilar in KOREA
Overarching Guideline
Guidelines on the Evaluation of Biosimilar Products (2009)
[Clinical Data]
Korea
EU (Reference Information)
The clinical comparability studies
include pharmacokinetic,
pharmacodynamic, and efficacy
studies. If the comparability can
be demonstrated by confirmatory
pharmacokinetic/pharmacodyna
mic data, an efficacy study may
be omitted.
For recombinant proteins, comparative
efficacy clinical trials usually are
necessary to demonstrate clinical
comparability. The clinical requirements depend
on the existing knowledge about the reference
product and the claimed therapeutic
indication(s).
For recombinant proteins, a biosimilar’s
immunogenicity must always be
investigated.
Immunogenicity risks in different indications
should be considered separately.
43. Guideline on Biosimilar in KOREA
Overarching Guideline
Guidelines on the Evaluation of Biosimilar Products (2009)
[Extrapolation of Indication]
Korea
EU (Reference Information)
Extrapolation of these data to other
indications of the reference product for which
post-marketing survey was completed
may be possible if all of the following
conditions are fulfilled:
For recombinant proteins, in certain
cases, it may be possible to extrapolate
therapeutic similarity to other indications.
Justification of extrapolation
depends on clinical experience, available
literature, whether the same
mechanism of action or receptor is
involved in both indications, and
possible safety issues in different
subpopulations.
A sensitive clinical test model has
been used that is able to detect potential
differences between the biosimilar
product and the reference product;
The clinically relevant mechanism of
action and/or involved receptor(s) are
the same;
Safety and immunogenicity have been
sufficiently characterized.
44. Guideline on Biosimilar in KOREA
Overarching Guideline
Guidelines on the Evaluation of Biosimilar Products (2009)
[PV and RMP]
Korea
Safety data obtained from clinical trials are
usually sufficient for product authorization,
but further close monitoring of clinical
safety of the biosimilar product is usually
necessary in the post-marketing phase.
EU (Reference Information)
By law, a risk management plan or
pharmacovigilance plan must be
submitted for biosimilars as for other
medicines. The plan should take into
account risks identified during product
development and potential risks and how
those risks will be addressed after
authorisation For recombinant proteins,
clinical safety must be monitored
closely after authorisation. The
application should include a risk
specification and pharmacovigilance plan.
46. Guideline on Biosimilar in ASEAN – SINGAPORE & MALAYSIA
SINGAPORE
MALAYSIA
GUIDANCE ON MEDICINAL PRODUCT
REGISTRATION IN SINGAPORE
GUIDANCE DOCUMENT FOR APPLICANTS :
(APPENDIX 17 GUIDANCE ON REGISTRATION OF
SIMILAR BIOLOGICAL PRODUCTS IN SINGAPORE)
INFORMATION AND SUBMISSION REQUIREMENTS
FOR REGISTRATION OF BIOSIMILARS
[Choice of Reference Product]
SINGAPORE
The reference product must
be registered in
Singapore.
MALAYSIA
EU
(Reference Information)
The reference product must
Must be authorised in the
be registered in Malaysia. EU based on a complete
dossier.
47. Guideline on Biosimilar in ASEAN – SINGAPORE & MALAYSIA
SINGAPORE
MALAYSIA
GUIDANCE ON MEDICINAL PRODUCT
REGISTRATION IN SINGAPORE
GUIDANCE DOCUMENT FOR APPLICANTS :
(APPENDIX 17 GUIDANCE ON REGISTRATION OF
SIMILAR BIOLOGICAL PRODUCTS IN SINGAPORE)
INFORMATION AND SUBMISSION REQUIREMENTS
FOR REGISTRATION OF BIOSIMILARS
[Quality Requirement]
SINGAPORE
MALAYSIA
EU
(Reference Information)
Comparability data between
the biosimilar product and the
reference product (in terms of
quality) must be submitted in
the quality dossier. The extent of
the comparability studies and the
assessment criteria depends on the
complexity of the product and the
capability of the methods used to
demonstrate comparability. The
comparability exercise should entail
evaluation of both drug substance
and drug product.
A full quality dossier is always
required. In addition,
extensive data focused on
the similarity, including
comprehensive side-byside physicochemical and
biological characterisation
of the biosimilar and the
reference product should be
submitted
For recombinant proteins, an
extensive comparability
exercise is required. Quality
aspects of comparability must be
considered in relation to
implications for safety and
efficacy. Purity and impurity
profiles of the active substance
and medicinal product must be
assessed qualitatively and
quantitatively for the biosimilar
and the reference product.
48. Guideline on Biosimilar in ASEAN – SINGAPORE & MALAYSIA
SINGAPORE
MALAYSIA
GUIDANCE ON MEDICINAL PRODUCT
REGISTRATION IN SINGAPORE
GUIDANCE DOCUMENT FOR APPLICANTS :
(APPENDIX 17 GUIDANCE ON REGISTRATION OF
SIMILAR BIOLOGICAL PRODUCTS IN SINGAPORE)
INFORMATION AND SUBMISSION REQUIREMENTS
FOR REGISTRATION OF BIOSIMILARS
[Nonclinical Data]
SINGAPORE
MALAYSIA
EU (Reference
Information)
In vitro studies: Assays like receptor-binding
studies or cell-based assays should
normally be undertaken in order to
establish comparability in reactivity and
the likely causative factor(s) if comparability
cannot be established. Animal studies should
be performed to investigate pharmacodynamic
effect/ activity relevant to the clinical
application, non-clinical toxicity as determined
in at least one repeat dose toxicity study,
including toxicokinetic measurements, and
specific safety concerns.
Safety pharmacology, reproduction toxicology,
mutagenicity and carcinogenicity studies are
not required for biosimilar products, unless
indicated by the results of repeat dose studies.
▶
„ In vitro studies:
Receptor-binding studies or cellbased assay should be conducted
▶
„ In vivo studies:
- Animal pharmacodynamic study
where approriate, relevant to clinical
use
- At least one repeat-dose toxicity
study
Other toxicological studies, including
safety pharmacology, reproductive
toxicology, mutagenicity and
carcinogenicity studies are not
required for biosimilar unless
warranted by the results from
repeated toxicological studies.
Non-clinical studies for
biosimilar versions of
recombinant proteins should
be comparative in nature,
designed to detect differences
in response between the
biosimilar and the reference
product.
In vitro studies, in vivo
studies in relevant animal
species, and at least one
repeat-dose toxicity study
in relevant animal species
normally should be conducted.
49. Guideline on Biosimilar in ASEAN – SINGAPORE & MALAYSIA
SINGAPORE
MALAYSIA
GUIDANCE ON MEDICINAL PRODUCT
REGISTRATION IN SINGAPORE
GUIDANCE DOCUMENT FOR APPLICANTS :
(APPENDIX 17 GUIDANCE ON REGISTRATION OF
SIMILAR BIOLOGICAL PRODUCTS IN SINGAPORE)
INFORMATION AND SUBMISSION REQUIREMENTS
FOR REGISTRATION OF BIOSIMILARS
[Clinical Data]
SINGAPORE
The clinical comparability exercise should begin with
pharmacokinetic (PK) and pharmacodynamic (PD)
studies followed by clinical efficacy and safety studies.
Comparative PK studies designed to demonstrate
clinical comparability between the biosimilar product
and the reference product with regard to key PK
parameters are required. Pharmacodynamic studies to
demonstrate therapeutic efficacy of the product is
required.
The immunogenicity of a biosimilar product
must always be investigated. The assessment of
immunogenicity requires an optimal antibody testing
strategy, characterisation of the observed immune
response, as well as evaluation of the correlation
between antibodies and pharmacokinetics or
pharmacodynamics, relevant for clinical safety and
efficacy in all aspects.
MALAYSIA
EU (Reference
Information)
Comparative pharmacokinetic
studies should be conducted to
demonstrate the similarities in
pharmacokinetic (PK) characteristics
between biosimilar and the reference
product. Clinical efficacy trials
should also be coundcuted.
Other PK studies such as interaction
studies or other special populations
(e.g children, elderly, patients with
renal or hepatic insufficiency) are
usually not required.
Studies should demonstrate clinical
sfaety and immunogenicity of the
drug product.
For recombinant proteins,
comparative efficacy
clinical trials usually are
necessary to demonstrate
clinical comparability. The clinical
requirements depend on the
existing knowledge about the
reference product and the
claimed therapeutic indication(s).
For recombinant proteins, a
biosimilar’s immunogenicity
must always be investigated.
Immunogenicity risks in different
indications should be considered
separately.
50. Guideline on Biosimilar in ASEAN – SINGAPORE & MALAYSIA
SINGAPORE
MALAYSIA
GUIDANCE ON MEDICINAL PRODUCT
REGISTRATION IN SINGAPORE
GUIDANCE DOCUMENT FOR APPLICANTS :
(APPENDIX 17 GUIDANCE ON REGISTRATION OF
SIMILAR BIOLOGICAL PRODUCTS IN SINGAPORE)
INFORMATION AND SUBMISSION REQUIREMENTS
FOR REGISTRATION OF BIOSIMILARS
[Extrapolation of Indication]
SINGAPORE
MALAYSIA
EU (Reference
Information)
In case the reference medicinal product has more
than one indication, the efficacy and safety of the
biosimilar product has to be justified or, if
necessary, demonstrated separately for each of
the claimed indications. In certain cases it may
be possible to extrapolate therapeutic
similarity shown in one indication to other
indications of the reference medicinal product.
Justification will depend on e.g., clinical
experience, available literature data, whether
or not the same mechanisms of action or the
same receptor(s) are involved in all
indications. Possible safety issues in different
subpopulations should also be addressed.
Demonstration of
similarity may also
allow
extrapolation of
efficacy and safety
data to other
indications of the
reference product.
For recombinant proteins, in
certain cases, it may
be possible to extrapolate
therapeutic similarity
to other indications.
Justification of
extrapolation depends on
clinical experience, available
literature, whether the same
mechanism of action or
receptor is involved in
both indications, and
possible safety issues in
different subpopulations.
51. Guideline on Biosimilar in ASEAN – SINGAPORE & MALAYSIA
SINGAPORE
MALAYSIA
GUIDANCE ON MEDICINAL PRODUCT
REGISTRATION IN SINGAPORE
GUIDANCE DOCUMENT FOR APPLICANTS :
(APPENDIX 17 GUIDANCE ON REGISTRATION OF
SIMILAR BIOLOGICAL PRODUCTS IN SINGAPORE)
INFORMATION AND SUBMISSION REQUIREMENTS
FOR REGISTRATION OF BIOSIMILARS
[PV&PMP]
SINGAPORE
MALAYSIA
EU (Reference Information)
ADR reporting,
PSURs, Risk
management plan,
Educational Materials
and Product Sales
Data for the
biosimilar product is
required
The pharmacovigilance, as
part of a comprehensive
RMP, should include
regular testing for
consistent manufacturing
of the biosimilar.
The pharmacovigilance
plan must be approved
prior to approval of
product and the system
must be in place to
conduct monitoring.
By law, a risk management plan or
pharmacovigilance plan must be submitted
for biosimilars as for other medicines. The plan
should take into account risks identified during
product development and potential risks and how
those risks will be addressed after authorisation.
For recombinant proteins, clinical safety must be
monitored closely after authorisation. The
application should include a risk specification and
pharmacovigilance plan.
52. Guideline on Biosimilar in ASEAN – SINGAPORE & MALAYSIA
SINGAPORE
MALAYSIA
GUIDANCE ON MEDICINAL PRODUCT
REGISTRATION IN SINGAPORE
GUIDANCE DOCUMENT FOR APPLICANTS :
(APPENDIX 17 GUIDANCE ON REGISTRATION OF
SIMILAR BIOLOGICAL PRODUCTS IN SINGAPORE)
INFORMATION AND SUBMISSION REQUIREMENTS
FOR REGISTRATION OF BIOSIMILARS
[PV&PMP]
SINGAPORE
MALAYSIA
EU (Reference
Information)
A product is interchangeable with another if both
products are approved for the same indication, and
can be used for the said indication. Two products are
substitutable with each other if they can both be used in lieu
of the other during the same treatment period. For
interchangeable products, one or the other can be used
(prescribed) but these products cannot be substituted with
one another during a treatment period. Interchangeability
does not imply substitutability.
Unlike generic chemical drugs, whereby the chemical
structure is identical to that of the reference chemical product,
a biosimilar product does not usually have an identical
structure to the reference biological product. Therefore, even
though a biosimilar product may be approved to be similar in
terms of quality, safety and efficacy to the reference product,
immunogenicity may preclude switching between products.
Given current
science,
biosimilars
cannot be
considered interchangeable with
the reference
product or products
of the same class.
Substitution is
determined at the
member state level, and
therefore this topic is not
directly addressed
in EMA guidance.
EMA guidance states that
biosimilars are not generic
medicinal products and that
the decision
to treat a patient with a
reference product or a
biosimilar should be made
following the opinion
of a qualified healthcare
professional.
54. Executive Summary – Regulation & Guideline
<Regulation & Guideline>
Topic
Reference
EU
US
JAPAN
Directive 2001/83/EC
The Biologics Price
Competition and
Innovation Act of 2009
(sections 7001 to 7003 of
the Patient Protection and
Affordable Care Act, Pub.
L. 111-148 (2010)).
Ministry of Health Labor
and Welfare,
Pharmaceutical and Food
Safety Bureau, Guideline
for Ensuring Quality,
Safety, and Efficacy for
Biosimilar Products,
PFSB/ELD Notification
No. 0304007.
▶
„ Guideline on Similar
Biological Medicinal Products
EMEA/CHMP/437/04.
▶
„ Guideline on Similar
Biological Medicinal Products
Containing BiotechnologyDerived
Proteins as Active Substance:
Nonclinical and Clinical Issues
EMEA/CHMP/BMWP/42832/20
05.
▶
„ Guideline on Similar
Biological Medicinal Products
Containing BiotechnologyDerived Proteins as Active
Substance: Quality Issues
EMEA/CHMP/BWP/49348/2005
.
▶
„ Guideline on
Immunogenicity Assessment of
Biotechnology-Derived
Therapeutic Proteins
EMEA/CHMP/BMWP/14327/06.
▶ Formal Meetings
Between the FDA and
Biosimilar Biological
Product Sponsors or
Applicants
▶ Quality Considerations
in demonstrating
biosimilarity to a reference
protein product
▶ Questions and Answers
▶ Scientific Considerations
in demonstrating
biosimilarity to a reference
product
Law
(Regulation)
Guideline
WHO
KOREA
ASEAN
MALAYSIA
Regulations on
Review &
Authorization of
Biological Products
(KFDA Notification
No. 2009-59)
WHO, Guidelines on
Evaluation of Similar
Biotherapeutic Products
(SBPs).
SINGAPORE
▶ Medicines Act
(Chapter 176)
▶ Poisons Act
(Chapter 234)
▶ Misuse of Drugs
Regulations –
subsidiary legislation
under the Misuse of
Drugs Act
(Chapter 185)
▶ Sale of Drugs Act
(Chapter 282)
▶ Medicines
(Advertisement and
Sale) Act
(Chapter 177)
Control of Drugs and
Cosmetic Regulations
1984 (CDCR 1984)
Guidelines on the
Evaluation of
Biosimilar Products
GUIDANCE ON
MEDICINAL PRODUCT
REGISTRATION IN
SINGAPORE
- APPENDIX 17
GUIDANCE
DOCUMENT FOR
APPLICANTS :
INFORMATION AND
SUBMISSION
REQUIREMENTS FOR
REGISTRATION OF
BIOSIMILARS
55. Executive Summary – Reference Product
<Reference Product>
Topic
Reference
EU
Must be authorised in the
EU based on a complete
dossier.
Reference
Product
US
Must be licensed
under a full
biologics licence
application (under
section 351(a) of the
Public Health Service
Act).
JAPAN
Must be
authorized in
Japan.
WHO
Should be authorised
in the country or
region in question (or,
where the licensing
country lacks an
authorised reference
product, should be
authorised and widely
marketed in another
jurisdiction with a wellestablished regulatory
framework for and
experience in evaluation
and post-market
surveillance of
biotherapeutics).
KOREA
The reference product
should be authorized
in Korea. However, if
the registered
reference product is
not available in Korea
commercially, the same
biological product as
the one authorized in
Korea (including the
manufacturing site and
the manufacturing
process) may be
purchased from
overseas markets and
used as the reference
product.
ASEAN
SINGAPORE
The reference
product must be
registered in
Singapore
MALAYSIA
The reference
product must be
registered in
Malaysia
56. Executive Summary – Quality
<Quality>
Topic
Quality
Requirement
Reference
EU
US
For recombinant proteins,
an extensive
comparability exercise
is required. Quality
aspects of comparability
must be considered in
relation to implications for
safety and efficacy. Purity
and impurity profiles of the
active substance and
medicinal product must be
assessed qualitatively and
quantitatively for the
biosimilar and the
reference product.
Unless the Secretary
makes a
determination that it
is unnecessary, an
application must
contain data from
analytical studies
demonstrating that
the biosimilar is
highly similar to
the reference
product
(notwithstanding
minor differences in
clinically inactive
components).
JAPAN
A biosimilar must
be fully
characterised,
including by
conducting studies
comparing the
structure and
composition,
physicochemical
properties,
bioactivity, and
immunologic
properties of the
biosimilar against
its reference
product.
WHO
Comprehensive
physicochemical and
biological
characterisation of
the biosimilar in
head-to-head
comparisons with the
reference product is
required, and all aspects
of quality and
heterogeneity
should be assessed.
KOREA
A complete description
of the manufacturing
process for the drug
substance and drug
product should be
provided in detail
including information
on quality
control/quality
assurance, in-process
controls, and process
validation.
Comparability study
along with
specifications,
analytical
procedures and
stability study
should be
conducted.
ASEAN
SINGAPORE
MALAYSIA
Comparability
data between the
biosimilar
product and the
reference product
(in terms of
quality) must be
submitted in the
quality dossier.
The extent of the
comparability
studies and the
assessment criteria
depends on the
complexity of the
product and the
capability of the
methods used to
demonstrate
comparability. The
comparability
exercise should
entail evaluation of
both drug
substance and drug
product.
A full quality dossier
is always required. In
adiition, extensive
data focused on
the similarity,
including
comprehensive
side-by-side
physicochemical
and biological
characterisation of
the biosimilar and the
reference product
should be submitted.
57. Executive Summary – Nonclinical Data
<Nonclinical Data>
Topic
Nonclinical
Data
Reference
EU
US
JAPAN
WHO
Non-clinical
studies for
biosimilar versions
of recombinant
proteins should
be comparative
in nature,
designed to detect
differences in
response between
the biosimilar and
the reference
product.
In vitro studies, in
vivo studies in
relevant animal
species, and at
least one
repeat-dose
toxicity study in
relevant animal
species normally
should be
conducted.
Unless the Secretary
makes a determination
that it is unnecessary, an
application must include
data derived from animal
studies (including the
assessment of toxicity)
to help demonstrate
that the product is
biosimilar to a
reference product.
It is important to
understand the
limitations of such
animal studies (e.g.,
small sample size, intraspecies variations) when
interpreting results
comparing the proposed
product and the
reference product. A
sponsor may be able to
provide a scientific
justification for a
stand-alone
toxicology study
using only the
proposed product
instead of a
comparative
toxicology study. For a
more detailed discussion
on the design of animal
toxicology studies, see
ICH S6/S6(R1).
Before performing
clinical studies, the
biosimilar applicant
must conduct nonclinical studies to
verify that the
product can be
safely administered
to humans. Before
conducting nonclinical studies, a
biosimilar must be
subjected to a full
quality
characterisation.
The
pharmacological
action of the
biosimilar and its
reference product
should be compared
through nonclinical
pharmacological
studies, and
repeat-dose
toxicity and
toxicokinetic
studies may be
useful.
The non-clinical
evaluation should
include
pharmacodynamic,
pharmacokinetic, and
comparative
repeat-dose
toxicity studies in a
relevant species.
The amount of
additional non-clinical
data required is
dependent on
product-specific
factors.
In vitro assays like
receptor binding
studies or cell-based
assays should
normally be
conducted to
establish
comparability of
pharmacodynamic
activity. Animal
studies in a relevant
species should
generally be
conducted.
KOREA
▶
„ In vitro studies:
Assays, such as receptorbinding studies or cellbased assays should
normally be
undertaken in order
to establish the
comparability of the
biological/
pharmacodynamic
activity of the biosimilar
product and the
reference product.
should be conducted
▶
„ In vivo studies:
- Animal studies should
be performed in species
know to be relevant
- At least one repeatdose toxicity study
- Other toxicological
studies, including safety
pharmacology,
reproductive toxicology,
mutagenicity and
carcinogenicity studies
are not required for
biosimilar unless
warranted by the results
from repeated
toxicological studies.
ASEAN
SINGAPORE
MALAYSIA
In vitro studies: Assays
like receptor-binding
studies or cell-based
assays should normally
be undertaken in order
to establish
comparability in
reactivity and the likely
causative factor(s) if
comparability cannot be
established.
Animal studies should be
performed to investigate
pharmacodynamic effect/
activity relevant to the
clinical application, nonclinical toxicity as
determined in at least
one repeat dose
toxicity study, including
toxicokinetic
measurements, and
specific safety concerns.
Safety pharmacology,
reproduction toxicology,
mutagenicity and
carcinogenicity studies are
not required for biosimilar
products, unless indicated
by the results of repeat
dose studies.
▶
„ In vitro studies:
Receptor-binding
studies or cell-based
assay should be
conducted
▶
„ In vivo studies:
- Animal
pharmacodynamic
study where
approriate, relevant
to clinical use
- At least one
repeat-dose
toxicity study
Other toxicological
studies, including
safety pharmacology,
reproductive
toxicology,
mutagenicity and
carcinogenicity
studies are not
required for biosimilar
unless warranted by
the results from
repeated toxicological
studies.
58. Executive Summary – Clinical Data
<Clinical Data>
Topic
Clinical
Data
Reference
EU
US
JAPAN
WHO
For recombinant
proteins,
comparative
efficacy
clinical trials
usually are
necessary to
demonstrate
clinical
comparability. The
clinical
requirements
depend on the
existing knowledge
about the reference
product and the
claimed therapeutic
indication(s).
For recombinant
proteins, a
biosimilar’s
immunogenicity
must always be
investigated.
Immunogenicity
risks in different
indications
should be
considered
separately.
Unless the Secretary
makes a determination
that it is unnecessary, an
application must include
data derived from a
clinical study or studies
(including the
assessment of
immunogenicity and
pharmacokinetics or
pharmacodynamics) that
are sufficient to
demonstrate safety,
purity, and potency in
one or more
appropriate
conditions of use for
which the reference
product is licensed and
intended to be used.
The purpose of these
data is to help
demonstrate that the
product is biosimilar to a
reference product.
Clinical studies
should generally be
required, but they
may not be
required
where nonclinical data are
sufficient to
assure
bioequivalence
and quality
equivalence (if
bioequivalence and
quality equivalence
have
been
demonstrated).
Pharmacokinetic or
pharmacodynamic
study results are,
however,
inconclusive
concerning clinical
efficacy. Clinical
studies should be
conducted to
verify efficacy for
the specific
indications for
which the
biosimilar
applicant
seeks
authorisation.
Clinical studies should
be designed to
demonstrate
comparable safety
and efficacy of the
biosimilar and
reference product.
Clinical trials are
required to
demonstrate similar
efficacy.
Immunogenicity
should always be
investigated in
humans before
authorisation.
KOREA
The clinical comparability
studies include
pharmacokinetic,
pharmacodynamic, and
efficacy studies. If the
comparability can be
demonstrated by
confirmatory
pharmacokinetic/phar
macodynamic data,
an efficacy study may
be omitted.
ASEAN
SINGAPORE
MALAYSIA
The clinical comparability
exercise should begin with
pharmacokinetic (PK) and
pharmacodynamic (PD)
studies followed by clinical
efficacy and safety studies.
Comparative PK studies
designed to demonstrate
clinical comparability
between the biosimilar
product and the reference
product with regard to key
PK parameters are
required.
Pharmacodynamic studies
to demonstrate
therapeutic efficacy of
the product is required.
The immunogenicity of
a biosimilar product
must always be
investigated. The
assessment of
immunogenicity requires
an optimal antibody
testing strategy,
characterisation of the
observed immune
response, as well as
evaluation of the
correlation between
antibodies and
pharmacokinetics or
pharmacodynamics,
relevant for clinical
safety and efficacy in all
aspects.
Comparative
pharmacokinetic
studies should be
conducted to
demonstrate the
similarities in
pharmacokinetic (PK)
characteristics
between biosimilar
and the reference
product. Clinical
efficacy trials
should also be
coundcuted.
Other PK studies such
as interaction studies
or other special
populations (e.g
children, elderly,
patients with renal or
hepatic insufficiency)
are usually not
required.
Studies should
demonstrate clinical
sfaety and
immunogenicity of
the drug product.
59. Executive Summary – Extrapolation of Indication
<Extrapolation of Indication>
Topic
Extrapolation
of Indication
Reference
EU
US
JAPAN
WHO
For recombinant
proteins, in certain
cases, it may
be possible to
extrapolate
therapeutic
similarity
to other indications.
Justification of
extrapolation
depends on clinical
experience,
available
literature, whether
the same
mechanism of
action or receptor
is involved in
both indications,
and possible safety
issues in different
subpopulations.
The sponsor will need
to provide sufficient
scientific justification
for extrapolating
clinical data to
support a
determination of
biosimilarity for each
condition of use for
which licensure is
sought. Such
scientific justification
should address, for
example, the
following issues for
the tested and
extrapolated
conditions of use.
The MOA(s) in
each condition of
use for which
licensure is sought.
The PK and biodistribution of the
product in
different patient
populations; PD
measures may
provide important
information on the
MOA.
Extrapolation
may be permitted
if the mechanism of
action is not
unclear, the
applicant can show
that a similar
pharmacological
result can
be expected for the
relevant indications,
and the
mechanism of
action does not
differ among
indications.
Extrapolation may
be possible if a
sensitive clinical test
model has been used
that is able to detect
potential differences
between the
products, that the
mechanism of
action and/or
receptors are the
same, and that the
safety and
immunogenicity
of the biosimilar have
been characterised
and there are no
special safety
issues expected with
the extrapolated
indication.
KOREA
Extrapolation of these
data to other indications
of the reference product
for which postmarketing survey was
completed may be
possible if all of the
following conditions are
fulfilled:
- A sensitive clinical
test model has been
used that is able to
detect potential
differences between the
biosimilar product and
the reference product;
- The clinically relevant
mechanism of action
and/or involved
receptor(s) are the
same;
- Safety and
immunogenicity have
been sufficiently
characterized.
ASEAN
SINGAPORE
MALAYSIA
In case the reference
medicinal product has
more than one indication,
the efficacy and safety of
the biosimilar product has
to be justified or, if
necessary, demonstrated
separately for each of the
claimed indications. In
certain cases it may be
possible to extrapolate
therapeutic similarity
shown in one indication
to other indications of
the reference medicinal
product. Justification will
depend on e.g., clinical
experience, available
literature data, whether
or not the same
mechanisms of action
or the same receptor(s)
are involved in all
indications. Possible
safety issues in different
subpopulations should also
be addressed.
Demonstration of
similarity may also
allow extrapolation
of efficacy and safety
data to other
indications of the
reference product.
60. Executive Summary – Naming
<Naming>
Topic
Naming
Reference
EU
To support
pharmacovigilance
monitoring, the
specific medicinal
product given to the
patient should be
clearly identified. The
name, appearance,
and packaging of a
biosimilar medicine
should differ from
those of the
reference product.
US
Not addressed.
JAPAN
WHO
Notification PFSB/EKD No.
0304011
regulates the naming of
biosimilars and
states that the nonproprietary names
and proprietary names of
biosimilars should be
readily distinguishable
from the names of
reference products and
other biosimilars. For nonproprietary names, the
following should be
added to the end of the
non-proprietary name:
Follow-on 1 [2, 3, and so
on].
For proprietary names, the
letters BS should be added
to the end of the name,
along with the dosage form,
dosage, and name of the
manufacturer.
Biosimilars should be
clearly identifiable by
a unique proprietary
name. Where an
international
nonproprietary name
(INN) is defined,
that name should be
stated and the WHO’s
policy on INNs should
be followed.
KOREA
Not Adressed
ASEAN
SINGAPORE
MALAYSIA
Not Adressed
All biosimilars
should be
distinguishable by
name i.e assign a
brand name explicitly,
using names that are
not suggestive
towards the
originator nor
towards other
biosimilars.
61. Executive Summary – Labeling
<Labeling>
Topic
Reference
EU
Not addressed.
Labeling
US
Not addressed.
JAPAN
Not addressed.
WHO
The prescribing information for the
biosimilar should be as similar as
possible to that of the
reference product, except for
product-specific information, such as
different excipient(s).
If the biosimilar has fewer indications
than the reference product, the
information related to those indications
may be omitted unless it is considered
important to inform doctors and patients
about certain risks. In these cases, the
prescribing information should clearly
state that the biosimilar is not indicated
for use in the specific indication(s) and
the reasons for it.
A national regulatory authority may
choose to require prescribing
information to mention the product is a
biosimilar, discuss the studies
performed with the biosimilar, and/or
include instructions to the physician on
how to use the biosimilar.
KOREA
Not Adressed
ASEAN
SINGAPORE
MALAYSIA
Not Adressed
It is expected that the labeling
of biosimilar meet the
following criteria:
- A clear indication that the
medicine is a biosimilar of a
specific reference product
- The invented name,
common or scientific name
and the manufacturer’ name
s
- Clinical data for the
biosimilar describing the
clinical similarity (i.e safety
and efficacy) to the reference
product and in which
indication(s)
- Interchangeability and
substitution advice should
clearly and prominently
state that the biosimilar is
not interchangeable or
substitutable with the
reference product.
62. Executive Summary – Pharmacovigilance and risk
<Pharmacovigilance and risk>
Topic
Pharmaco
-vigilance
and risk
Reference
EU
US
JAPAN
WHO
By law, a risk
management plan or
pharmacovigilance
plan must be
submitted for
biosimilars as
for other medicines.
The plan should take
into account risks
identified during
product development
and potential risks and
how those risks will be
addressed after
authorisation
For recombinant
proteins, clinical
safety must be
monitored closely
after authorisation.
The application
should include a risk
specification and
pharmacovigilance
plan.
The Secretary’s existing
authority to require a
risk evaluation and
mitigation strategy
(REMS) for drugs
applies to
biosimilars (a REMS
documents
requirements designed
to minimise risk
associated with a
drug).
In addition, the
Secretary’s existing
authority to mandate
post-market studies
and clinical trials as
well as post-market
labelling changes
applies to biosimilars.
A post-marketing
safety surveillance
plan and a risk
management plan
for biosimilars is
required and should
be submitted with the
application.
A pharmacovigilance
plan is required when an
application is submitted
and a risk management
plan may be necessary in
some cases.
KOREA
Safety data obtained
from clinical trials are
usually sufficient for
product authorization,
but further close
monitoring of clinical
safety of the
biosimilar product is
usually necessary in
the post-marketing
phase.
ASEAN
SINGAPORE
MALAYSIA
ADR reporting,
PSURs, Risk
management
plan, Educational
Materials and
Product Sales Data
for the biosimilar
product is required.
The pharmacovigilance,
as part of a
comprehensive RMP,
should include regular
testing for consistent
manufacturing of the
biosimilar.
The
pharmacovigilance
plan must be
approved prior to
approval of product and
the system must be in
place to conduct
monitoring.
63. Executive Summary – Interchangeability and substitution
<Interchangeability and substitution>
Topic
Interchangeability
and
substitution
Reference
EU
US
Substitution is
determined at
the member
state level, and
therefore this
topic is not
directly
addressed
in EMA guidance.
EMA guidance
states that
biosimilars are
not generic
medicinal
products and that
the decision
to treat a patient
with a reference
product or a
biosimilar should
be made
following the
opinion
of a qualified
healthcare
professional.
Substitution is
determined at state level
in accordance with state
pharmacy laws.
FDA must find a
biosimilar to be
interchangeable with its
reference product if the
information submitted by
the biosimilar applicant
demonstrates that:
▶
„ The applicant’s product is
biosimilar to the
reference product (under
the law’s standard
for biosimilarity).
▶
„ The applicant’s product
can be expected to produce
the same clinical result as
the reference product in
any given patient.
For products administered
more than once to an
individual, the applicant
must also demonstrate
that the risk in terms of
safety or diminished
efficacy of alternating or
switching between use of
the biosimilar and use of
the reference product is not
greater than the risk of
using the reference product
without such alternation or
switch.
JAPAN
WHO
Substitution of a Not
biosimilar for, or addressed.
the combined use
of a biosimilar
with, a reference
product should
be avoided
during the
postmarketing
surveillance
period.
KOREA
ASEAN
SINGAPORE
Not
A product is interchangeable
Addressed with another if both products
are approved for the same
indication, and can be used for
the said indication. Two products
are substitutable with each other if
they can both be used in lieu of the
other during the same treatment
period. For interchangeable
products, one or the other can be
used (prescribed) but these
products cannot be substituted
with one another during a
treatment period.
Interchangeability does not imply
substitutability.
Unlike generic chemical drugs,
whereby the chemical structure is
identical to that of the reference
chemical product, a biosimilar
product does not usually have an
identical structure to the reference
biological product. Therefore, even
though a biosimilar product may be
approved to be similar in terms of
quality, safety and efficacy to the
reference product, immunogenicity
may preclude switching between
products.
A warning statement on the risks
associated with switching of
products during treatment, and
against product substitution, is to
be included in the package insert
of the biosimilar product.
MALAYSIA
Given current
science,
biosimilars
cannot be
considered
interchangeable with
the reference
product or
products of the
same class.
64. Executive Summary – Data protection for originators
<Data protection for originators>
Topic
Data
protection for
originators
Reference
EU
US
JAPAN
WHO
For a reference product for
which the application
for approval was
submitted in October or
November 2005 or later
(different rules apply to
a reference product for
which the application for
approval was submitted
earlier), a biosimilar may
not be marketed until
ten years after
authorisation
of its reference product
that is a new active
substance. This period
may be extended for an
additional year, if within
eight years after reference
product authorisation, the
reference product
is authorised for a new
therapeutic indication
that constitutes a
significant clinical benefit
in comparison with
existing therapies.
A biosimilar may not be
approved until 12 years after
the date on which the
reference product was first
licensed under section 351(a) of
the Public Health Service Act.
The date of first licensure does
not include the date of approval
of a supplement to the reference
product application or the date of
approval of a subsequent
application for either:
„A change to the reference
product, other than a structural
change, that results in a new
indication, route of
administration, dosing schedule,
dosage form, delivery system,
delivery device, or strength.
„A structural modification to the
reference product that does not
result in a change in safety,
purity, or potency.
A biosimilar
application cannot
be approved until the
innovative product on
which the application
relies has completed
an eight-year reexamination or
post-marketing
surveillance
period.
Not Addressed
KOREA
Not Addressed
ASEAN
SINGAPORE
MALAYSIA
Not Addressed
Not Addressed
65.
66. Biosimilar Guideline in Latin
American Countries
Mr. Daniel Guedes
Bio-Manguinhos / FIOCRUZ / Brazil
68. Biosimilar Guideline in Latin American Countries
FIOCRUZ / Bio-Manguinhos
Institute of Technology in Immunobiologicals
Vaccines
Reactives
Biopharmaceuticals
69. Biosimilar Guideline in Latin American Countries
FIOCRUZ / Bio-Manguinhos
Vaccines
Diphtheria, Tetanus, Pertussis and Hib;
Yelow Fever;
Haemophilus influenzae b;
Meningitis A e C;
Poliomyelitis;
Measles, Mumps and Rubella.
Tetravalent viral (SmallPox).
70. Biosimilar Guideline in Latin American Countries
FIOCRUZ / Bio-Manguinhos
Reactives
Molecular
Tests
NAT HIV/HCV;
Rapid Tests
DPP HIV, Syphilis, Canine Leishmaniasis, Leptospirosis;
71. Biosimilar Guideline in Latin American Countries
Reactives
Parasitological Tests
Sorological Tests
Kato-Katz
Imunoenzimatic
C. Leishmaniasis
Ind.
Immunofluorescence
C. Leishmaniasis
H. Leishmaniasis
Chagas Disease
72. Biosimilar Guideline in Latin American Countries
Biopharmaceuticals
Alphapoetin
Alphainterferon
73. Biosimilar Guideline in Latin
American Countries
Daniel Guedes, Ph.D.
Quality Control Department
FIOCRUZ / Bio-Manguinhos - Brazil
74. Latin American Countries Pharmacopoeia
Argentina
Farmacopoea Argentina
Brazil
Farmacopéia Brasileira
Chile
Chilean Pharmacopoeia Foundation
México
Farmacopea de los Estados
Unidos Mexicanos
75. NATIONAL HEALTH SURVEILLANCE AGENCY COLLEGIATE
BOARD – ANVISA (BRAZIL)
Integration of Latin American countries Pharmacopeias;
Optimize the use of resources and knowledge;
Mercosur`s Pharmacopoeia
78. Biosimilar Guideline in Latin American Countries
Guidelines from Argentina
Law 16.643
ANMAT
7075/2011
Biologicals
3397/2012
Biotechnologicals
7729/2011
Biosimilars
1490/1992
79. Biosimilar Guideline in Latin American Countries
Guidelines from Argentina
Law 16.643
“Are subject to this law and regulations, import, export, production,
preparation, processing, commercialization or deposit in national
jurisdiction or interprovincial trade of drugs, chemicals, reagents,
pharmaceutical forms, diagnostic elements, and all other product use
and application in human medicine and people whether natural or
involving in such activities.
All this products shall meet the conditions set in Argentina`s
Pharmacopoeia.”
80. Biosimilar Guideline in Latin American Countries
Guidelines from Argentina
Rule 7075/2011
Establish the conditions and requirements for registration of medical
specialties with biological origin.
81. Biosimilar Guideline in Latin American Countries
Guidelines from Argentina
Rule 3397/2012
Authorization Biotechnology products
Monoclonal antibodies;
Recombinant products;
82. Biosimilar Guideline in Latin American Countries
Guidelines from Argentina
Rule 7729/2011 – Authorization Biosimilars
Medical specialty of biological origin with previous marketing.
Comparability referential product;
Characterization with modern methods;
Similar behavior to the referential product;
83. Biosimilar Guideline in Latin American Countries
NATIONAL HEALTH SURVEILLANCE AGENCY
COLLEGIATE BOARD – ANVISA (BRAZIL)
RDC 46 / 2000
RDC 55 / 2010
RDC 49 / 2011
RDC 61 / 2008
RDC 50 / 2011
RDC 17 / 2010
RDC 233 / 2011
84. Biosimilar Guideline in Latin American Countries
RDC 46/ 2000
Regulates production processes
and quality control, acquisition
and distribution of medicines for
human use.
85. Biosimilar Guideline in Latin American Countries
RDC 61/ 2008
Provides on Criteria for
Harmonization of Nomenclature of
Vaccines and Serums.
86. Biosimilar Guideline in Latin American Countries
RDC 17/ 2010
Requirements for the Good
Manufacturing Practice in
Medicinal Products for human
87. Biosimilar Guideline in Latin American Countries
RDC 55 / 2010
Provides on the registration of
new biological products
(Biosimilar) and biological
products.
88. Biosimilar Guideline in Latin American Countries
RDC 55, Scope
I. Vaccines;
II. Hyper-immune serums;
III. Hemoderivatives;
IV. Biodrugs (Biologicals or by Biotechnology);
V. Monoclonal antibodies;
VI. Drugs (live, attenuated or dead microorganisms).
89. Biosimilar Guideline in Latin American Countries
RDC 49 / 2011
Provides on post-registration changes and
inclusions, suspension and reactivation of
manufacturing and cancellations of biological
product registration.
90. Biosimilar Guideline in Latin American Countries
RDC 50 / 2011
Stipulates the procedures and conditions for
conducting stability studies for registration or
changes post-registration of biological
products.
91. Biosimilar Guideline in Latin American Countries
RDC 233 / 2011
Technical Regulation of Production and Quality
Control for Registration, Changing PostRegistration and Revalidation of Allergen Extracts
and Products.
92. Biosimilar Guideline in Latin American Countries
Conclusions
The WHO Biosimilar Guidelines influenced Latin America;
The structure is similar to those of USP;
There are new but consistent Guidelines for Biosimilars;
More countries can join the group.
96. Impact of Product Variants on
Product Functional Activity and
Stability in the Content of
Biosimilars
Anita Krishnan, Ph.D.,
Lupin Limited
97. Overview of Product and Process inter-relationship
Acceptable ranges for a subset of these QAs are normally established based on a
combination of clinical experience, pre-clinical studies, lab studies and prior knowledge.
The acceptable ranges are used to establish the boundaries for the design spaces in the
Upstream, Downstream and Drug Products sections of the case study.
98. Critical Quality Attributes
“A CQA is a physical, chemical, biological, or microbiological property or
characteristic that should be within an appropriate limit, range, or distribution to
ensure the desired product quality. Desired product quality includes clinically safe
and efficacious product.” ICH Q8 (R2)
Product-Related Substances
• Glycosylation variants (Galactose; Man5; Sialic Acid; Afucose)
• Acidic Variants (Deamidated/Sialylated Species)
• Oxidation
• Unpaired cysteine residues
• C-terminal Lysine Variants
10
Aggregation & Clips
Glycosylation
Product-Related Impurities
• Clips / Truncations
• Aggregates
5
Oxidation
Process-Related Impurities
• Residual Protein A (Affinity Resin)
• Host Cell Proteins
• DNA
• Endotoxin/Bioburden/Particulates/Viruses
1
Deamidation
Q cyclization
Lys variants
In the case of Biosimilars most of the CQAs are available as prior art.
99. CQAs related to Fab variations
Deamidation
Glycation
CQAs related to Fc effector functions
Gal content and CDC
Afucose and ADCC
FcRn and PK
100. IgG Sequence analysis for Fab CQAs
Asn 30 to Asp
CDR 1
CDR 2
Fab glycosylation : N-X-S/T
CDR 3
K glycation
Fab related
variations
Asn 55 to Asp
CDR 1
CDR 2
CDR 3
Asp 102 to isoAsp
101. CQAs Related to Fab Variations
Asp30
isoAsp102
R. J. Harris et al. / J. Chromatogr. B 752 (2001)
233 –245
Reaction of primary amines of lysine residues with
reducing sugars such as glucose/lactose to form
aldimine (Schiff’s base ) and later a ketoamine adduct
102. Molecular Signatures of Fc effector Functions
Fcɣ R I, II, III
FcRn - Met256
Fcɣ R I, II, III
HINGE
C1q
C1q
FcRn – His protonation
DP
Deamidation
104. Role of neonatal Fc receptor (FcRn) in PK
Regulates systemic half-life by
salvaging FcRn bound IgG and
recycling
IgG:FcRn interaction depends on
conserved His in CH2-CH3 interface
Salt bridges between positive
residues of IgG and negative amino
acids on FcRn surface
109. Optimized Process: 10L Bioreactor
Mannosylation
Galactosylation
CDC:
RMP
INIT
OPT
RMP
Afucosylation
ADCC:
131%
RMP
OPT
96 % 92 %
INIT
OPT
Fucosylation
270%
INIT
G0F
G1F
G1’F
G2F
R O I R O I R O I R O I
110. Oxidation of rHu mAb – reduced binding to Protein A
30000
uV
25000
20000
15000
Oxidized impurities
10000
mAb-RMP
In-house 1
In-house 2
5000
0
5.0
10.0
15.0
20.0
25.0
30.0
5% TBHP
1% TBHP
3% TBHP
0.5% TBHP
Oxidized
Native
35.0
min
111. Site Specific Oxidation of rHu mAbs on chemical stress
MWD: Signal A, 214 nm/Bw:4 nm
Rituximab RMP Ctrl
Rituximab RMP Ctrl.dat
1200
MWD: Signal A, 214 nm/Bw:4 nm
MWD: Signal A, 214 nm/Bw:4 nm
MWD: Signal A, 214 nm/Bw:4 nm
MWD: Signal A, 214 nm/Bw:4 nm
rituximab rmp 0.5 a
rituximab rmp 0.25_a
rituximab rmp 0.125_a
rituximab rmp 1_a
1200
Resolution (DAB)
1000
1000
37°C CTRL
1.0% t-BHP
0.5% t-BHP
0.25% t-BHP
0.125% t-BHP
LC
800
Fc/2
Fd
600
600
400
400
Ox Fc/2
200
200
0
0
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
mAU
800
112. Site Specific Oxidation of in-house samples
MWD: Signal A, 214 nm/Bw:4 nm
dp5 500 mgper50ml_3m at_a
1200
MWD: Signal A, 214 nm/Bw:4 nm
dp6 100 mgper10ml_3m rt_a
RMP
Inhouse 1
Inhouse 2
1000
LC
800
Fc/2
Fd
mAU
600
400
Ox Fc/2
200
Ox Fd
0
Oxidation of methionines in Fc and Fd
-200
27
28
29
30
31
32
33
Minutes
34
35
36
37
38
39
40
41
42
43
114. Risk based approach for prevention of Oxidation
• Enhanced oxidation due to presence of dissolved oxygen
• Metal-catalyzed oxidation is site-specific - Copper induced
catalysis observed (Baker et al 1978)
• Photo-oxidation of Met can form persulfoxide/ Met sulfoxide
• Oxidation due to compromised thermal stability
115. Dissolved Oxygen (%)
Dissolved oxygen induces oxidative damage
Nitrogen purging reduces dissolved oxygen
Before
After
Storage for 12h
DO after 12h
96%
0%
Open to air
25%
97%
0%
Headspace with
Nitrogen
2%
117. Structure based sequence alignment of the C1q complex
components
D270
C1q binding epicentre
Stretch of charged residues
P331
K322 P329
Proline sandwich
W87
W110
Van der Waals contacts
Hydrogen bonds
NATURE |VOL 406 | 20 JULY 2000
118. Site directed mutagenesis for enhanced activity
Enhanced ADCC
(Increased FcɣRIII a binding)
IgG1 Fc
CH2
C1q binding
Site
Enhanced CDC
(Increased C1q binding)
Sugar
Chain
CH3
FcɣRIII
binding
Site
FcRn binding
Site
Improved PK
(Increased FcRn binding)
119. Critical Attributes to be assessed for Biosimilars
Post-translational Modifications
POTENCY
EFFICACY
IMMUNOGENICITY
SAFETY
3 D structure
Protein aggregates
Three properties of therapeutic proteins – in the opinion of FDA
cannot be sufficiently measured but are deemed to be important for
understanding the behaviour of protein drugs: post-translational
modifications, three-dimensional structures and protein aggregation.
120. Conclusions
• Glycosylation has a direct overbearing effect on potency (ADCC
and CDC)
• Oxidation of Met 256 and 432 have been proved to have a role in
FcRn binding and therefore PK
• Oxidation of Met has a definite role in CDC activity too
• Reasons for reduced potency could be due to multiple factors
namely Oxidation, Tertiary structure differences and Reduced
CD20 binding
• Risk based approach to control oxidation levels and introduction
of stability and release methods for oxidation in mAbs
121.
122. New USP Bioassay Chapters
Tina S. Morris, Ph.D.,
Vice President, Biologics & Biotechnology,
USP
123. USP Bioassay Chapters
Official since 1950:
<111>: Design and Analysis of Biological Assays
– A major revision will be proposed in Pharmacopeial Forum PF39(4)
The new suite:
<1030>: Biological Assay Chapters – Overview and Glossary
– Will be official with the 2nd Supplement of USP36
<1032>: Design and Development of Biological Assays
<1033>: Validation of Biological Assays
<1034>: Analysis of Biological Assays
Official
All of these chapters are focused on relative potency bioassays.
Chapter numbering is important…
124. From General to Specific – Biological Potency
<1030> Overview of Bioassay
<1032>
Development
of Biological
Assays
<1034>
Analysis of
Biological
Assays
<111> Design and
Analysis of
Biological Assays
<121> Insulin
Assays
Insulin Monograph
<1033>
Validation of
Biological
Assays
Guidance &
Information
General
Requirement
Product-Specific
Requirement
Product Quality
Attributes
125. <1032> Design and Development of Biological Assays
Focuses on design and development, rather than analysis
Covers animal assays, cellular assays, enzyme assays and
immunoassays
Focuses on design elements, theory and practice
– e.g., describes good and bad plate designs
Addresses activities throughout the product life cycle
Some key ideas
–
–
–
–
fitness for use, different applications of assay
biological and statistical assay fundamentals
assay from design and development through validation and
performance monitoring
system and sample suitability
126. <1032> Design and Development of Biological Assays
Specific points:
Identify and minimize sources of variability in a method
Record cell line information, before banking, including...
–
–
–
–
–
–
–
–
identity
morphology
purity
cryopreservation
thaw and culture conditions
thaw viability
growth characteristics
functional stability
Prepare two-tiered bank: Master and Working
– the size of the banks depends on the growth characteristics of the cells,
the number of cells required for each assay, and how often the assay will
be performed
127. Chapter <1032>’s Recommendations for Standards
Where possible, a Standard should be prepared using the same
manufacturing process as the drug substance
Storage conditions may vary from drug substance or product:
– Temperature (e.g., –70 °C or –20 °C instead of 2–8 °C)
– Container (e.g., plastic vials instead of syringes)
– Formulation (e.g., lyophilized formulation or addition of carrier proteins)
Test Standard for stability at appropriate intervals
An initial Standard = Primary Standard
Subsequent Standards = Working Standards
– Separate SOPs usually required
– Trend charts may be useful in identifying the cause of assay drift
128. <1033> Validation of Biological Assays
Describes approaches for validation design (sample selection and
replication strategy), validation acceptance criteria, data analysis
and interpretation, and bioassay performance monitoring through
quality control
Validation parameters discussed include relative accuracy,
specificity, intermediate precision, and range
– Laboratories may use dilutional linearity to verify the relative accuracy
and range of the method
– Although robustness is not a requirement for validation, <1033>
recommends that a bioassay’s robustness be assessed either prevalidation or with additional experiments soon after validation
Some differences from common practice:
– Equivalence testing
– Confidence intervals to demonstrate conformance to acceptance
criteria
129. <1034> Analysis of Biological Assays
Intended to be useful for biologists and statisticians alike but
heavier on the statistics side
Covers models for different types of bioassays
– linear and nonlinear
– parallel line and slope ratio
– Quantal (e.g., yes/no assays)
Develop and elaborate on appropriate uses of equivalence
assessment; e.g. for parallelism/similarity
Have also developed a 4PL Bioassay Simulator that lives on
the www.usp.org/usp-nf/compendial-tools website and is
freely available to the public. Other simulators are in
development
– Please provide feedback on your needs!
130. Plan for Revisions to <111>
Include only components that USP intends to be
required or that are commonly needed in
monographs:
– Outliers
– Combination of independent assays
– Confidence Intervals
Revision is on track for publication in PF39(4)
issue, appearing in July-August 2013, with
public comment period closing September 30,
2013
131. Product-Specific Potency Assays
Can be called out in a Monograph or General Chapter
Monograph requirements supersede Chapter
Requirements
A potency test or at least bioidentity test based on a
functional assay is required for most biologics and
biotechnology-derived medicines licensed for the US
market. A few smaller proteins/peptides have only
HPLC-based Assays to determine potency (e.g.,
vasopressin, oxytocin, leuprolide, etc.)
132. Europe and the US Differ in Bioassay Requirements
In Europe, for peptides and small proteins that are
considered “well-characterized” neither a unit-based
quantitative bioassay nor a bioidentity test are
required. This is not the case in the US.
Some examples:
– Insulin(s) - US requires bioidentity based on USP <121>
Insulin Assay: rabbit blood glucose test
– Somatropin - US requires rat weight gain bioidentity test
– Glucagon - US requires primary rat liver cell bioidentity
assay, see USP <123>Glucagon Bioidentity Tests
133. Compendial Implications
Many bioassays and bioidentity tests for
licensed biologics are still animal-based
Associated concerns:
Assays with generally high variability and poor
precision
Challenges in unit assignments and maintenance,
especially in relationship to the International Unit
where it exists
Ethical issues regarding animal use
134. USP Initiative: Replacement of Animal Assays
Current: <126> Somatropin Bioidentity Tests – USP is
evaluating a cell-based assay using a nonproprietary cell
line available from commercial sources. The chapter will
contain the animal test and the cell assay.
Future:
– <123> Glucagon Bioidentity Tests – USP is working with a
sponsor to add a cell-based assay to this chapter and
distribute the necessary cell line as a Reference Standard
– <121> Insulin Assays – USP has reached out to sponsors for
suitable cell-based assay for insulins and hopes to revise the
chapter with one or more in the future
135. Case Study: Somatropin Bioidentity Test
Official in the Somatropin monographs since 2005 for
bioidentity (to assure potency of the material now assigned by
an HPLC Assay method; previously the rat method was used
to assign potency)
Currently official method uses hypophysectomized rats
injected with somatropin for 10 days. Body weight change is
measured and potency calculated relative to the USP
Somatropin RS
Two sponsors came forward with new cell-based methods.
– Both validated and accepted by FDA for use with US-approved
products
– Bridging to the animal methods was submitted by the sponsors
– Verification of method performance and suitability performed in USP
laboratory
– Most robust method was chosen for development of a new chapter
<126>Somatropin Bioidentity Tests, using commercially available,
nonproprietary cell line
136. Cell-based Bioidentity Test Format
Uses the cell line Nb2-11 derived from a rat
lymphoma
Proliferation of the cells is dependent on factors
such as prolactin, IL-2, or hGH
The method is based on measurement of ATP
production in response to Somatropin (rhGH)
treatment relative to the USP Somatropin RS. The
amount of intracellular ATP is directly proportional
to the proliferation of the cells due to the hGH
treatment.
137. Cell-based Bioidentity Test Format
On the day of the assay, cells are harvested, washed, and
seeded in 96-well assay plates in a minimal medium
containing 1% horse serum for one hour.
A dilution series of either Somatropin test sample or USP
Somatropin RS (or positive and negative controls) is
delivered and the cells are incubated for ~30 hours
A luminescent cell substrate solution is added for ~30 min
then the luminescence in the wells is measured
Relative potency is calculated using parallel line analysis
relative to the USP Somatropin RS
To pass bioidentity, a somatropin sample must possess not
less than 2 USP Somatropin Units/mg
139. Data Summary and Next Steps
The cell-based method has good signal-to-noise ratios,
averaging between 5 and 6
Percent RSD’s were generally below 5%.
Little plate-to-plate variability
Plate uniformity analyses performed in the USP laboratory
suggested a slight edge effect in the left-most column and
upper-most rows of the microtiter plates, but based on the
analyses there was no significant impact on the results. The
sponsor did not see any uniformity issues.
The sponsor has successfully used the Nb2-11 cells for the
procedure through 50 passages. The USP confirmed the
method consistency through passage 16 (which was 11
passages post-thaw).
140. Data Summary and Next Steps, cont’d.
Overall, the cell-based method provides a more precise,
consistent, and reliable method when compared to the in
vivo method
The new chapter <126>Somatropin Bioidentity Tests will be
proposed in the PF39(5) issue, appearing September 2013.
Public comments are open through November 30, 2013
Collaborative laboratory testing of the USP Somatropin RS
for this new purpose will occur in parallel and be complete
prior to the chapter moving to official
141. Epoetin – The Commutability Challenge
For epoetin special challenges exist in the transition
from in vivo to in vitro assays
Different types of in vitro assays have varying
degrees of sensitivity to and correlation with
glycosylation (esp. sialylation) differences
In vivo to in vitro transition, equivalence
determination and unit transition has to occur on an
assay-by-assay basis
142. <124> Epoetin Bioassays – What are the Options?
Option 1: include both in vivo and in vitro assays
– In vivo assay: include only normocythemic assay
– Potential misuse of in vitro assay to inappropriately assign units of
activity to EPO preparations.
– Which in vitro assay to include? The proposed cell assay is not the
actual assay used for product release
Option 2: include only the in vivo assay with guidance on
– How the standard can be used in an in vitro assay (acceptance
criteria for in vitro to in vivo activity ratios)
– How to assign an in vitro unitage to the USP standard, so that the in
vitro assay can be used to assign units to EPO preparations
Both options assume that the monograph refers to chapter
<124> for assay requirements
143. Path Forward and Future Opportunities
Recommendation for a Path Forward
– Move forward with option 2, and publish <124> in PF, with in
the in vivo assay only. This will provide strict guidance on the
use of both in vivo and in vitro bioassays to measure the
biological activity of erythropoietin (EPO) and will preserve the
traceability to the WHO International Standard for EPO
– In a second phase, develop a cell-based assay to be included in
the chapter. Other cell assays can be used provided that these
assays are validated against compendial assays
– Physico-chemical assays that can predict outcome of bioassays
can also be added in the future.
144. Expert Panel Discussions – Chapter <124>
USP EPO for bioassay RS calibrated against 3rd WHO
International Standard for EPO by in vivo mouse bioassay
– assigned unitage in International Units (IU) of EPO
Calibration strategy means that USP EPO for bioassay RS
can be used directly in in vivo mouse bioassay for
calibration of any process-specific EPO preparation.
An in vitro bioassay cannot be used to transfer the unitage
from the USP EPO for bioassay RS to a process-specific
EPO preparation
– Unless you demonstrate that the USP EPO for bioassay RS
and the process-specific EPO preparation exhibit an
equivalent ratio of in vitro to in vivo potency.
145. Expert Panel Recommendations – Chapter <124>
The ratio of in vitro to in vivo activity is generally
inversely correlated with the degree of terminal
sialylation, thus highly sialyated products have a
higher level of in vivo activity and as such, have a
relatively lower ratio of in vitro to in vivo activity.
Different manufacturing processes mean that the
degree of terminal sialylation can be highly variable
from one EPO preparation to another.
– To use an in vitro assay to measure the biological activity of
a preparation of EPO, you must have a full understanding of
the relationship between its in vivo and in vitro activity.
• Include with the USP EPO for bioassay RS, in both the in vivo
assay and in a specific in vitro assay.
146. Expert Panel Recommendations – Chapter <124>
The USP EPO for bioassay RS is assigned a unitage
which represents its activity in both in vivo assays and in
vitro assays.
– If the ratios of in vitro to in vivo potency for the material being tested and
the USP EPO for bioassay RS are equivalent, then the USP EPO for
bioassay RS can be used directly in the in vitro assay to calibrate the
material being tested.
– However, if these ratios are not equivalent, then the standard cannot be
used with its assigned in vitro potency in the in vitro assay.
– Instead, the ratio determined for the material being tested should then be
used to assign a process-specific, in vitro assay unitage to the USP EPO
for bioassay RS. The USP EPO for bioassay RS, with its adjusted in vitro
assay unitage, can then be used in the in vitro assay to transfer the
unitage from the USP EPO for bioassay RS to the material being tested.
147. Modernizing Compendial Bioassay/Bioidentity Tests: Challenges
For small proteins or peptides: when can a bioassay be
replaced by a physicochemical method? And, can the
method stand alone or is bioidentity assurance needed?
Assays for biological products with more than one activity
Commutability of assays and reference materials
Availability of public methods and data:
– Intellectual property barriers
Equivalence determination between assays:
– Challenges in establishing equivalent results between
different biological systems: animal vs. cell-based assays vs.
physico-chemical, etc.