Biologics and Biosimilars

Regulatory Process and Roadmap

Sada Siva, RAC-Drugs,

RA Specialist (Biologics CMC),
Analytical Scientist (SME/Product Development)
This Discussion covers….
 Overview of Biosimilar (& Biologics)
 Important Regulatory considerations
 Important CMC requirements
 Important Non clinical requirements
 Important Clinical requirements
This Discussion covers….
 Overview of Biosimilar (& Biologics)
 Important Regulatory considerations
 Important CMC requirements
 Important Non clinical requirements
 Important Clinical requirements
Biosimilar - Definitions
 Biosimilars are subsequent entry Biologics to approved ones.
 Different names: Biosimilars/ Follow on biologics/similar
biologics/ subsequent entry biologics/Similar biotherupetic product
 EMA: A 'biosimilar‘ is a biological medicine that is similar to existing
biological medicine authorised .
 FDA: Biosimilarity is defined in section 351(i) of the PHS Act to mean
that the biological product is highly similar to the reference product
notwithstanding minor differences in clinically inactive components and
that there are no clinically meaningful differences between the biological
product and the reference product in terms of the safety, purity, and
potency of the product.
 This is critical to understand the differences between
Pharmaceutical drugs (small molecules), Biologics,
Biosimilars and Generics /ANDA before going further, which
are outlines in next slides.
 Biologic Drugs Vrs Chemical Drugs
Aspects Biologics Drugs Small Pharmaceutical drugs
Molecule size & Large to Very large (around 15000- Smaller (around 10-500 daltons) and
Structure 250000 daltons) and Complex structure simple structure
Mode of Actions Highly specific to Targets Less specific to Targets
Immunogenic while administration Not Immunogenic while
administration
Regulatory Should demonstrate that the drug is safe Should demonstrate that the drug is
expectations , pure and Potency safe , pure and strength
Manufacturing Complex process-Produced in living Produced using chemical synthesis,
Process systems and sensitive to small changes in well standardized & controlled process
process impacts product quality &Safety and less sensitive to small changes in
(Process validation required before BLA) process
(Process validation can be provided
later)
Characterization Very complex to fully characterize the Easy to Characterize the molecules
molecules, often requires orthogonal with available analytical technology.
and modern techniques for the same.
 Biologic Drugs Vrs Chemical Drugs
Aspects Biologics Drugs Small Pharmaceutical drugs
Stability Sensitive to storage-Full Real time data Relatively more stable- Partial Real
required for shelf life determination, no time data is okay for shelf life
extrapolation (potency tests are required determination, extrapolation is possible
in release and stability) using Accelerated stability
Sterility Terminal sterilization is not possible, Terminal sterilization is possible.
need other smooth sterilization like
filtration.
- More suspetable to contamination , so - Less prone to Contamination
more care to be taken to ensure absence
of contamination (aseptic processing)
Regulatory US- 351a as per PHS act (BLA) US- 505 b(1) as per FDC act (NDA)
pathway EMA-Article 8 (MAA) EMA-Article 8 (MAA)
 Biologic Drugs Vrs Biosimilar Drugs
Aspects Biologics Drugs Biosimilar Drugs
Application Full application Abbreviated Application
Regulatory data Should demonstrate that the drug is safe Should demonstrate that the drug is having
expectations , pure and Potent by using Full CMC, similar safety , purity and Potency with
non clinical and non clinical data. that of approved original Biologic (RMP).
CMC/Quality -Full Quality information of critical -Full Quality information of critical
Intermediates, DS and DP. Intermediates, DS and DP.
-Analytical Similarity (Pivotal)
NC data Required as per ICHS6 Minimal/abbreviate-to be discussed case
by case)
Clinical data Phase 1 (Safety, Pk and PD) Minimal/abbreviate (comparative Phase 1
Phase 2 (Dose, safety and efficacy) and phase 3 to show safety and efficacy
phase 3 (safety and efficacy) similarity with Reference product)
To reduce the uncertainty , to be discussed
case by case to avoid longer studies.
Regulatory US- 351a as per PHS act (BLA) US- 351k as per PHS act (BLA) EMA-
pathway EMA-Article 8 (MAA) Article 10(4) (MAA)
Biologic Drugs Vrs Biosimilar Drugs
FDA View Generic Drugs Vrs Biosimilar Drugs
Differences in Data requirements between New
Biologic and Biosimilar molecules
 Biosimilars approval process-
key considerations
 The process depends mainly depends on Country/Market/Region:
 Regulated markets with clear established and strict Regulatory requirements
(Europe/EMA , USA , Australia, Canada and japan)
 Semi regulated markets – Regulatory requirements are available but not very well
established/not very strict (eg: India, Latam, Asean, GCC country's)
 Other small Country's – Relies on Approval of above country/WHO Guidelines
 EMA and US FDA regulatory information is outlined in further slides
 Few Important Considerations w.r.to SRM/ROW markets
 Most of country's don’t have clear regularity path/regulations and expectations on
Biosimilar CMC and Clinical data requirements.
 Regulatory scrutiny levels are vary drastically by region or Country (GMP
Inspection & Assessments)
 Review timelines are drastically difference from country to country
 Need to discuss with Local RA Agency/Affiliates to understand the landscape
 Country specific requirements- like Stability conditions , Prior approval in reference
country, RMP sourced from their country to discussed
 Biosimilars approval process-
key considerations
 Pre submission requirements of Biosimilar Application
 Development of Robust manufacturing process Biosimilar (Consult Agencys, if required)
 Collect the required Data (CMC, Non clinical and Clinical) to show Bio similarity
 Country/Region specific requirement (Module 1 & Technical /release /Specific if any)
 Submit Clinical studies–IND/IMPD application prior to execution
 Submit the Application (BLA/MAA) for marketing purpose
 Biosimilar Application-Review phase
 Address Agency's queries promptly throughout the review phase
 Inspection readiness (Share manufacturing schedules)
 Label and Names negotiations to finalize the same.
 Negotiations on any post approval data requirements
 Post Approval requirements of Biosimilar Application
 Pharmacovigilance (report any safety or adverse events timely)
 Update any changes to submitted information (Variations/ Supplements).
 Interchangeability – Switching studies to assure no safety risk and reduction in efficacy
 GMP inspections and License Renewals at regular intervals
Biosimilars approval in Europe
 EU Regulatory body-EMA has very well established Biosimilar
pathway and approved first biosimilar molecule in world.
 Biosimilars approval is regulated by European medicines agency
(EMA) & CHMP (committee for human medicinal products).
 Legal Basis: Directive 2001/83/EC , Regulation 726/2004
 First approved Biosimilar:
 Omnitrope (somatropin) from Eli Lilly (in 2006 )
 Others Biosimilars: Around 80+ Biosimilars of below products
 Growth hormone, EPO, GCSF, Infliximab, Eternacept, Insulin,
Interferon, trastuzumab, Adalimumab and Beacizumab Etc..
Biosimilars submitted via
Centralized procedure in
EMA/Europe
Biosimilars –Agency interactions

 Interactions with Agency are very important tools in product

development to product approval
 Increases Success rates by aligning with Agency's expectations
 Helps to understand Agency expectations at the earliest
(prior to critical studies ) to optimise study outcomes
 To discuss innovative approaches /new technologies
 Discuss Critical challenges and sponser approaches adequacy
 Seek clarity on certain study/data expectations
 Biosimilars –Agency interactions in Europe
 Type of meetings are available as mentioned below:
A. Scientific Advices working part meeting
B. Parallel Consultation (between different member states or
country’s)
C. Parallel Scientific Advices meeting (For consulting US FDA
and EMA at a time)
D. Clarification meeting (Whenever some clarity required on
requested info required)
E. Innovative Task Force meeting (To discuss new advance
technologies- ATMPs).
F. Presubmission meeting (To ensure readiness and
conformance of dossier with legal and regularity
requirements).
G. Accelerated Assessment meeting (Request for Quick
Review with justification).
H. Name Review Group meeting (For Name request).
I. PRIME (Priority Medicine) Kickoff meeting.
Biosimilars approval in Europe
Biosimilars approval in Europe
Biosimilars approval in USA
 Biosimilars approval is regulated by US FDA under both PHS act
and FDC act.
 Legal Basis: BPCI Act under PHS act (351k path way)
 FDA has more delay in establishing a proper Biosimilars pathway
until 2009 –BPCI act (mostly follows similar standards to EMA in
terms of data requirements)
 First approved Biosimilar:
 rGCSF from Sandoz (in 2015 )
 Infliximab from Cellitron-First Biosimilar mAb in 2016
 Others Biosimilars: Around 30+ Biosimilars of below products
 Growth hormone, EPO, GCSF, Infliximab, Eternacept, Insulin,
Interferon, trastuzumab, Adalimumab and Beacizumab Etc..
Biosimilars approval pathways in USA
 FDA _Sponser interactions

 Sponsors has to utilise the opportunities to meet Agency at the

earliest to increase approval rate
 Discuss Development plans with Agency to take their feedback
to avoid challenges at late stage.
FDA Review Timelines
FDA- Post Approval changes reporting
This Discussion covers….
 Overview of Biosimilar (& Biologics)
 Important Regulatory considerations
 Important CMC requirements
 Important Non clinical requirements
 Important Clinical requirements
CMC data is very important

Drug used in clinical studies-Safe and effective

CMC helps maintain the connection in quality between the drug

used in clinical studies and the marketed drug

Drug marketed to consumers-Commercial product

Biologics/Biosimilar - Manufacturing
 Biologics/Biosimilars are outcome of complex manufacturing process.
Small change in process lead to difference in product quality and safety.
 Good understanding of manufacturing is critical to control the process and
produce the Consistent quality product. (CPP’s, IP controls and tests,
robust process ranges , QTPP , stable cell banks , sterile assurance etc to
be established )
 Good understanding of product is critical to perform the comparability
studies with Reference product and interpret the differences are clinically
meaningful or not . (Product CQA’s. structure to function relationship and
robust similarity design)
 Regulatory requirement (PHS Act): The facility in which the
biological product is manufactured, processed, packed, or held
meets standards designed to assure that the biological product
continues to be safe, pure, and potent.
 Know your Biosimilar product
and its complex manufacturing Process

1. CQA 3. Cell banks 4. Upstream 8. Scale up 10. RA submission

2. QTPP RCB –R&D 5. Downstream 9.Quality Control 11. Product Review
MCB -GMP 6.Formulation 12. Facility Review
WCB -GMP 7.Analytical 13. Approval
 Know your Biosimilar product
and its complex manufacturing Process
Cloning

Upstream
Process/
Cell culture

Downstream
Process/
Purification

Formula
tion and
Filling
 Know your Biosimilar product
and its complex manufacturing Process
 Important Factors for considerations for both
Biologics & Biosimilars Development
 The CMC or Quality requirements are same for both Biologics and
Biosimilars.
 Additionally Biosimilars need to provide Analytical comparability data
between RMP and Proposed Biosimilars
 Some important topics to be considers in CMC Developments:
 Cellbanks characterization and stability (MCB and WCB) to ensure desired
product quality is produced without adventicious contamination.
 Reference Standards establishment and qualifications – (PRS&SRS) serves a
control for quality between clinical and commercial batches.
 Robust Manufacturing process Development & Validations to produce consistent
quality product.
 Process Controls on Critical Intermediates, DS and DP (IPC & Release
specifications)
 Hold time and shelf life establishments
 Process and product related Impurities – Characterization and clearance studies
 Adventitious reagents control (Aseptic procedure/sterile assurance)
 Important Factors for considerations for both
Biologics & Biosimilars Development

 Storage containers -Container and closures compatibility

 Stability – Shelf life verification and understand degradation profiles.
 Pre License/Approval inspection (mandate for Biologics &
Biosimilars)
 GMP Inspection ready to ensure manufacturing capability to produce the
consistent product quality (& QMS system)
 Microbial controls strategies implemented for sterility Assurance.
 Data review for accuracy on Bio similarity studies and other information
Important Factors for considerations for
specially Biosimilars Development
 Reference Product – RMP should be from respective regions or
additional bridging studies required (3 way Analytical /PK studies)
 Reference Standards – Established at the earliest in Development.
 Expression system- Better to have same
 Manufacturing process – should be Robust and Consistent
 Analytical methods qualification and validations- happens early in
program (prior to Analytical comparability).
 Finished Drug Product formulation and CCS -Better to have same
formulation, however minor difference are allowed.
Important Factors for considerations for
specially Biosimilars Development
 Extensive Analytical Comparison Assessment should include
 Physicochemical Properties – extensive
 Functional Activities
 Receptor Binding and Immunochemical Properties
 Impurities – Process and Product
 Forced degration stability studies with Reference standard
 Results should be discussed w.r.to Clinical meaningful or not.
 Further Non clinical and clinical studies design based on Analytical
similarity outcome and residual uncertainty.
 Biosimilars- Analytical comparability study
 Regulatory requirement (PHS Act): The biological product is
biosimilar to a reference product based upon data derived from—
(aa) analytical studies that demonstrate that the biological product
is highly similar to the reference product notwithstanding minor
differences in clinically inactive components;
 Biosimilarity is comparison exercise between a proposed and reference
product. This plays critical role in Biosimilar approval.
 The aim of the Biosimilar exercise is to demonstrate that the Proposed product
and the reference medicinal product are similar at the level of the finished
product. It is not expected that all quality attributes of the biosimilar product
will be identical to RMP.
 Adequate Numbers of RMP and Biosimilar Lots should be used (atlease 10
RMP lots) across different age.
 Analytical methods with adequate sensitivity should be used
 However, where qualitative and/or quantitative differences are detected, such
differences should be justified and, where relevant, demonstrated to have no
impact on the clinical performance of the product.
Reference product Bridging Studies
This Discussion covers….
 Overview of Biosimilar (& Biologics)
 Important Regulatory considerations
 Important CMC requirements
 Important Non clinical requirements
 Important Clinical requirements
 Biosimilars- Non Clinical considerations
 The Objectives of Comparative Non Clinical studies are
 To reduce the uncertainty from Analytical similarity
 To show comparable toxicity with Reference product
 To show comparable PK/PD with Reference product
 To show comparable safety (Immunogenicity) with Reference product
 To show comparable Efficacy with Reference product
 Reduced non-clinical programme may be possible (and ethically maybe better
acceptable); should focus on the specific needs and mechanism of action (e.g. as
regards the requirement to show comparable impact on signalling events).
 A risk-based approach to evaluate mAb on a case-by-case basis is recommended
to decide on the choice and extent of in vitro and particularly in vivo studies.
 Relevant species should be selected to extrapolate the outcomes to humans.
 Most Common requirement is Comparative repeat toxicity study in relevant
species, other non clinical studies can be negotiated with Agency's case by case.
 Biosimilars- Non-Clinical considerations
New Biologics Biosimilars
Intial Safety Dose Yes No
Local Tolerance Yes Case by Case
PK (ADME) Yes No
Dose escalation studies Yes No
Toxicity –single dose Yes Yes
Toxicity –Repeat dose
Genotoxicity Yes No
Carcinogenicity Yes Case by Case
Reproductive toxicity Yes No
Pediatric studies Yes No
Immunogenicity Yes Case by Case
This Discussion covers….
 Overview of Biosimilar (& Biologics)
 Important Regulatory considerations
 Important CMC requirements
 Important Non clinical requirements
 Important Clinical requirements
Biosimilars- Clinical considerations
Biosimilars- Clinical considerations
 The Objectives of Comparative Clinical studies are
 To reduce the uncertainty from Analytical similarity
 To show comparable PK and/or PD with Reference product
 To show comparable safety (Immunogenicity) with Reference product
 To show comparable Efficacy with Reference product
 Biosimilar studies are relatively smaller compared Reference product
studies.
 If established markers are PD markers available, Comparative efficacy
studies may not required.
 Phase II studies are not required as the dose and administration is
same as Reference product.
 Extrapolation to other indications without additional clinical studies
based on scientific justification is possible.
Biosimilars- Clinical Data requirements with
PD markers/ with Efficacy
Biosimilars-Approved with(/out) PD markers
Interchangeable Biosimilars (FDA)
 Helps in Pharmacy level substation in US
 Additional Switching studies are required
 Some important points to consider about
Biosimilars are….
 Step wise Approach used to establish Bio similarity of products.
 Totality of evidence from all available studies used to approve Biosimilars.
 Approved Biosimilar are expected to have similar quality, safety and
efficacy as of reference product.
 Biosimilars don’t have to be proved for every indication. Extrapolation is
possible.
 Based on submission country, need to align with additional local
regulatory requirements if any.
 Biosimilar user fee Act (BisUFA)- gives option to consult with
FDA for discuss any aspects (BPD type 1-4 meetings)
 EMA gives scientific advices to asset developer incase of any
required feedback support.
 Some important points to consider about
Biosimilars are….
 Other than looking at the guidelines there are no requirements
for development / trials of biosimilars.
 Biosimilars must have comparable quality, safety and efficacy.
 Each Biosimilar will have gone through the appropriate
regulatory pathway.
 Every Biosimilar product is different and each should be
considered an individual brand in their own right.
 Because every biosimilar is different – no one set of regulatory
rules will work for all developing the need for each to be
considered on a case by case basis.
References….
 EMEA:Guideline on similar biological medicinal products
 EMEA:Guideline on similar biological medicinal products containing biotechnology-derived
proteins as active substance: non-clinical and clinical issues
 EMEA:Guideline on similar biological medicinal products containing monoclonal antibodies –
non-clinical and clinical issues)
 FDA:Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein Product to a
Reference Product
 FDA:Scientific Considerations in Demonstrating Biosimilarity to a Reference Product
 FDA:Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference
Product
 ICH guideline Q5E: Note for guidance on biotechnological/biological products subjected to
changes in their manufacturing process
 ICH guideline Q5C: Note for guidance on quality of biotechnological products: Stability testing of
biotechnological/biological products
 ICH guideline Q6B: Note For Guidance on Specifications: Test Procedures and Acceptance
Criteria for Biotechnological/Biological Products
 India DCGI: Guidelines on Similar biologics by CDSCO and DBT
 ICH Guideline: safety and efficacy guidelines
Backup slides
Reference medicinal Product (RMP)
 RMP used in Biosimilarity should be approved and licensed
by respective regulatory authority.
 Single sourced RMP should be used all the studies (Qualiy,
Non Clinical and Clinical studies )
 However, with the aim of facilitating the global development
of Biosimilars , it is allowed to compare the biosimilar with a
other regulatory authorised comparator.
 In this Case , A bridging comparability study (Analytical and
PK and or PD ) has to be performed between the two RMP
products along with Proposed Biosimilar product.
Reference Medicinal Product
 The reference medicinal product details should be captured
properly (Complete details like lot, source, presentation)
 Multiple different batches of the reference medicinal product
should be used and justified.
 The age of the different batches of reference medicinal
product (Wide range over expiry is recommended )
 Publicly available reference standards (e.g. Ph. Eur.) cannot
be used as the reference medicinal product for demonstration
of biosimilarity
Expression system

 Careful selection should be done to produce High similar

product .
 Expression system differences may results in undesired
consequences like atypical Glycosylation pattern, a
different impurity profile compared to RMP
 Better to choose the same expression system
Manufacturing process
 Develop a process to produce a Product highly similar to
RMP
 Quality Target for product profile (QTPP) should be
established at the early Development phase by RMP analysis
and publicly available in formation.
 Performance and consistency of the manufacturing process of
he biosimilar .
 Proper formulation should be selected .better to have the
same as RMP does not need to be identical.
 If a different formulation and/or container & closure system
, its impact on safety and efficacy should be justified
Assessment of Physicochemical Properties
 Extensive State of the art analytical tests should be used to
show Biosimilarity between the proposed product and the
reference product.
 Lots used for the analyses should support the Biosimilarity of
both the clinical material used in the clinical study(ies)
intended to support a demonstration of Biosimilarity
 Multiple representative lots should be used understand
the lot-to-lot variability of both products
 A risk-based assessment should be performed to
understand the impact and criticality of each
quality attribute on safety and efficacy.
Extensive analytical testing should cover
 Similarity at different levels should be shown which include
 Primary structures, such as amino acid sequence
 Higher order structures, including secondary, tertiary, and
quaternary structure (including aggregation)
 Enzymatic posttranslational modifications, such as
glycosylation and phosphorylation
 Other potential variations, such as protein deamidation and
oxidation
 Intentional chemical modifications, such as PEGylation sites
and characteristics
Analytical methods selection…
 Selection of tests chosen for comparability is mainly based on
characteristics of the protein product and its
potential impurities.
 Method to be used should have appropriate accuray,
sensitivity and specificity to provide meaningful
information as to whether the proposed product and the
reference product are highly similar.
 Unlike routine quality control assays, tests used to
characterize the product do not necessarily need to be
validated. Qualification is needed for characterization tests.
Analytical methods selection…
 It is often necessary to apply more than one analytical
procedure to evaluate the same quality attribute.
 Because they provide independent data to support the
quality of that attribute (e.g., orthogonal methods to assess
aggregation).
 In addition, the use of complementary analytical techniques
in series is encouraged , should provide a meaningful and
sensitive informaion for comparing products. (such as
peptide mapping combined with mass spectrometry of the
separated molecules)
Impurities…..
 The sponsor should characterize, identify, and quantify
impurities in the proposed product and the
reference product, to the extent feasible
 If a comparative physicochemical analysis reveals comparable
product-related impurities at similar levels between
the two products, no additional studies required.
 If proposed product different or higher levels of impurities
than in the RMP, then additional pharmacological
/toxicological or other studies may be necessary to
understand their impact.
Impurities…..
 It is preferable to rely on purification processes to remove
impurities . . . rather than to doing additional tesing.
 Differences that may have a safety advantage (e.g. lower
levels of impurities) should be explained.
 The process-related impurities in the proposed product are
not expected to match those observed in the reference
product. But they should be minimised by process.
 The potential impact of the differences in the impurity
profile upon safety should be addressed and supported by
appropriate data.
 Stability Data….
 Proposed Biosimilar & RMP degradation profiles should be
established .
 Accelerated and stress stability studies, as well as forced
degradation studies should be performed side by side.
 These comparative studies should be conducted under multiple
stress conditions (e.g., high temperature, freeze thaw, light
exposure, and agitation)
 Results should be presented and if these studies may reveal
product differences that warrant additional studies .
 Shelflife should be determined from the Realtime stability data of
the Proposed Biosimilar and extrapolation is no recommended.
(RMP in real time stability is not required for Biosimilarity)
Functional Activities
 Functional assays are imp part of Biosimilarity as an essence
step establishing complete characterization profile.
 These tests act to complement physicochemical analyses and
are a qualitative measure of the function of the protein
product.
 For complex proteins, the available analytical technology, the
physicochemical analysis may be unable to confirm the
integrity of the higher order structures. In his case
functional assays are very helpful.
Receptor Binding Properties
 Receptor Binding and Immunochemical Properties
 When binding or immunochemical properties are part of the
activity attributed to the protein product, analytical tests
should be performed to characterize the proposed product in
terms of these specific properties, (e.g., if binding to a
receptor is inherent to protein function, this property should
be measured and used in comparative studies)
Statistics recommended…
Some important points to consider about
Biosimilars are….
 Biosimilars don’t have to be proved for every indication.
 Other than looking at the guidelines there are no
requirements for development / trials of biosimilars.
 Biosimilars must have comparable quality, safety and efficacy.
 Each Biosimilar will have gone through the appropriate
regulatory pathway.
 Every Biosimilar product is different and each should be
considered an individual brand in their own right.
 Because every biosimilar is different – no one set of
regulatory rules will work for all developing the need for
each to be considered on a case by case basis.