biologics and biosimilars overview

8/20/2019 Biologics and Biosimilars Overview

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Biologics and biosimilars An overview

B i ol o gi c s an d b i o s i mi l ar s

A n ov e r v i e w



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Contents

An introduction to biotechnology ................................................................................3A brief history of medicine development...................................................................................4What are biologic medicines?...................................................................................................5How are biologic medicines developed?...................................................................................6The value of biotechnology.......................................................................................................8What are biosimilar medicines?..............................................................................................10How do biosimilars differ from the original innovator medicines? ..........................................11

The emerging role of biosimilars............................................................................................12

Regulating biosimilars ......................................................................................................13Approval pathways for biologic and biosimilar medicines ......................................................14Biosimilar regulations.............................................................................................................18

Pharmacovigilance and traceability .........................................................................21Naming, tracking and tracing medicines.................................................................................22

Substitution and interchangeability .........................................................................25The variation in global substitution guidelines.......................................................................26

Manufacturing biologics .................................................................................................31The manufacturing process is unique to every manufacturer ..................................................34Striving to ensure a consistent supply.....................................................................................35

Glossary ...................................................................................................................................37

Works cited.............................................................................................................................43

© 2012 Amgen Inc. All rights reserved. 12-12



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An introductionto biotechnology

A ni n t r o d u c t i on t o

b i o t e c h n ol o

g y



Anintroductionto

b i o t e c h n o l o g y

Amgen was one of the rst companies torecognize the potential of modern biotechnologyin developing valuable medicines for patients– and to assemble the diverse set of skillsnecessary to advance from hard to applied

science. A leader in biotechnology since 1980,Amgen is focused on serving patients bydiscovering, developing and manufacturinginnovative human therapeutics. By pioneeringthe development of novel products based onadvances in cellular and molecular biology,Amgen’s therapeutics have changed the practiceof medicine and helped millions of peoplearound the world to ght cancer, kidney disease,rheumatoid arthritis and other serious illnesses.



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An introductionto biotechnology

The term biotechnology wasrst coined in 1919 to describethe interaction between biologyand human technology for theconversion of raw materials intosocially valuable products.

At the time, the focus was on foodproduction but by the 1940s earlyadvances in the technology had ledto the development of medicines;

enabling the mass production ofantibiotics, such as penicillin,

which continue to be used tocontrol infectious diseases.

The breakthrough that laidthe groundwork for modernbiotechnology came when thestructure of DNA was discovered inthe early 1950s.

A standard denition ofbiotechnology was not reacheduntil the United Nations and WorldHealth Organization accepted the1992 Convention on BiologicalDiversity and dened biotechnologyas “any technological applicationthat uses biological systems, livingorganisms or derivatives thereof,to make or modify products andprocesses for specic use”. (1)



A brief history of

medicine developmentThe rst medicinal drugs came fromnatural sources and existed in theform of herbs, plants, roots, vinesand fungi. Until the mid-nineteenthcentury these natural remedies wereall that was available to treat someconditions. The rst synthetic drug,

chloral hydrate, was discovered in1869 and introduced as a sedative-hypnotic. The rst pharmaceuticalcompanies were spin-offs from thetextiles and synthetic dye industryand owe much to the rich source oforganic chemicals derived from thedistillation of coal (coal-tar). (2)

For many years, the pharmaceuticalindustry traditionally developedchemical drugs (also referred toas small molecules ), includingwell-known medicines such asacetylsalicylic acid, to treat a widerange of illnesses. Since the 1970s,a revolution in biotechnology hasresulted in a new class of medicine:the biologic.



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Acetylsalicylic acidSmall molecule

21 atoms

IgG1 antibodyBiologic medicine

> 20,000 atoms

What are biologicmedicines?A biologic medicine is a largemolecule typically derived fromliving cells and used in thetreatment, diagnosis or prevention

of disease. Biologic medicinesinclude therapeutic proteins, DNAvaccines, monoclonal antibodiesand fusion proteins. Biologicmedicines are often 200 to 1,000

times the size of a small molecule

drug and are far more complexstructurally. They are also highlysensitive, making them moredifcult to characterize andproduce. Due to both their sizeand sensitivity, biologic medicinesare almost always injected into apatient’s body.



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How are biologicmedicines developed?Biologic medicines are made

in living organisms to produceproteins to treat various diseases,often by genetically modifyingcell constructs or cell lines.DNA technology is often used toinsert desirable genes or removeundesirable ones within a livingcell or via a vector such as a virus,

prompting a specic function –such as the production of a proteinto treat disease. This relativelynew advance in biotechnologyhas led to the development ofmany of today’s most importantmedicines, including monoclonalantibodies for cancer, human

insulin for diabetes and the cloningof the naturally occurring protein,erythropoietin to stimulate theproduction of red blood cells in thetreatment of chronic anemia. (3)

The genetic code of a chosenprotein, such as human insulinor an immune system antibody,is identied and replicated by

combining different segments of

DNA to build a functional DNAsequence. The DNA sequence isintroduced into the host cell of aliving organism, such as bacteria,yeast or mammal cells, alteringthe cell’s genetic makeup andcoding it to produce the chosenprotein. Genetically modied cell

lines are carefully selected andcultured in large bioreactors beforethe biologic medicine is extractedthrough complex and lengthypurication processes.

Each step is intricate, sensitiveand often specic to a particularmedicine, requiring signicantskill and expertise. Even minoralterations may lead to changesin cell behavior and differencesin the structure, stability or otherquality aspects of the end product.Any of these differences have thepotential to affect the treatment’ssafety, efcacy and shelf life, andto increase the risk of an unwantedimmune response.

C

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Chromosome Gene

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The most effective cell line is selected forexpansion. During selection, the cells that canproduce the biologic most effectively are identiedand expanded to manufacture the medicine. This cellline is unique to each manufacturer and is the sourceof all future product.

The biologic is modied to ensure itfunctions as intended. Specic chemicalsare added to control the function of the biologic.

The unique cell line is grown inbioreactors and carefully monitored. The biologic drug is then isolated andpuried using sophisticated technology.

Translating high science: from laboratory to better patient care

01

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Biologic medicines are made in livingorganisms by genetically engineering DNA. DNA is inserted into living cells, such as bacteria,yeast or cultured animal cells, to code for theproduction of a particular protein.

Discover more on the manufacturing of biologicmedicines by visiting the Amgen YouTubechannel at youtube.com/user/Amgen



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The value of biotechnologyToday’s biologic medicines havemade a signicant difference to

the lives of patients with seriousillnesses, including cancer,blood conditions, auto-immunedisorders such as rheumatoidarthritis (RA) and psoriasis, andneurological disorders like multiplesclerosis. Recreating humanproteins into biologic medicines

has revolutionized how we treatdisease. (5)

Worldwide, nearly 200biologic medicines havetransformed the lives of over800 million patients withserious illnesses. (3)

By understanding the mechanismsof diseases, such as multiplesclerosis, biologic medicines canbe developed to target and modify

underlying causes of disease,

potentially altering the course ofdisease rather than simply treatingsymptoms. (6)

The development of new biologicmedicines may be the best hopefor effectively treating diseases forwhich there are currently no cures.

The mapping of the human genome– one of the most signicantadvances in biotechnology– has led to an escalation inbiotechnology research, includingexperimental therapies such asstem cell and gene therapy. Today,over 400 biologic medicinesworldwide are being studied inserious illnesses, such as HIV/ AIDS, Alzheimer’s disease, cancer,cardiovascular disease andautoimmune disorders. (3)



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A n i n t r o d u c t i o n t o

b i o t e c h n o l o g y

Targeting diseasepathways to

benet patients Cancer: Following cancerpathways and determining themolecular basis of cancer has ledto the development of new targeteddiagnostics and treatments.Traditionally, cancer has beentreated with surgery, radiation andchemotherapy. Biotechnology hascontributed to signicant advancesin cancer treatment, includinghormone therapies, biologicmedicines and targeted therapiessuch as monoclonal antibodies. (3)



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Biosimilars

What are biosimilar medicines?Unlike generic medicines where the activeingredients are identical, biosimilars – by

denition – are not likely to be identical tothe originator biologic. They are similar,but not the same. Biologics made bydifferent manufacturers differ from theoriginal product and from each other.

Biosimilars are not expected to bedirect copies of biologic medicines andare therefore not the same as genericdrugs. Due to the complex structure ofbiologic medicines and the processesinvolved in production, biosimilars mustbe shown on the basis of analytical,non-clinical and clinical data to besimilar to an original biologic in termsof structural characteristics, and safetyand efcacy. Minor differences withthe active ingredient are expected andpermitted so long as any such differencesare demonstrated not to be clinicallymeaningful. (7) The patents of a growingnumber of biologic medicines have alreadyexpired or are due to expire, which has ledto an increased interest in the developmentof biosimilars. (11)

Dening biosimilars The World Health Organization:“A biotherapeutic product which issimilar in terms of quality, safety andefcacy to an already licensed referencebiotherapeutic product.” (8)

The European Medicines Agency:A biological medicine that is developedto be similar to an existing biologicalmedicine (the ‘reference medicine’).When approved, a biosimilar’s variabilityand any differences between it and

its reference medicine will havebeen shown not to affect safety oreffectiveness.(9)

The U.S. Food and DrugAdministration: A biologicalproduct that is highly similar to a U.S.licensed reference biological product

notwithstanding minor differencesin clinically inactive components,and for which there are no clinicallymeaningful differences between thebiological product and the referenceproduct in terms of the safety, purityand potency of the product. (10)

Original biologic

Similar to snowakes, biosimilars from different manufacturers differ from theiroriginator biologic medicines and from each other



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How do biosimilarsdiffer from the originalinnovator medicines?The active ingredient of abiosimilar is expected to closelyresemble that of the original

biologic. Unlike generic medicines(small molecules) where theactive ingredient is required tobe identical, the manufacturingprocess through which a biologic(large molecule) is made cannotbe exactly duplicated by anothermanufacturer. (12)

There are naturally occurringdifferences between an originatorand biosimilar medicine:

• Biologic medicines are notmade using a set of standardmaterials, but are developedusing unique biological systems

and living cells. As a result, theactive ingredient is impossible torecreate exactly and the selectedcell lines from which the biologicmedicine originates are unique toeach manufacturer. (13)

• The manufacturing process forbiologic medicines is generallymore complex than manufacturingprocesses for chemical drugs.Unlike small molecule drugs,biologic medicines are producedin genetically-engineered livingcells that are sustained in ahighly-controlled environment.The protein produced by the cellswill be inuenced by individualcell characteristics as well asthe environment and nutrientsprovided.

• Each manufacturer has differentprocesses that create distinctivecharacteristics in the product,which are specic to themanufacturer. This creates aunique relationship between abiologic’s manufacturing processand the nal product approvedby regulators. (12)



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The emergingrole of biosimilarsCountries around the world face a

growing, aging population and anincrease in chronic disease. (14)Withexpanding demand for good-qualityhealthcare comes the challenge ofcontrolling healthcare expenditure.The safe and regulated introductionof biosimilars into the market hasbeen forecasted to increase access

to much needed biologic medicinesand reduce costs. (12)

Over the next few years, a newgeneration of complex biosimilarswill be developed as numerousleading biologic medicines,worth an estimated $81 billionin global annual sales, will lose

their patents by 2020. (15) Fusionproteins and monoclonal antibodiesused in cancer and autoimmunediseases are expected to forma substantial proportion of thisnew line of biosimilars. (16) TheEuropean Medicines Agency(EMA) is updating its guidelines

on biosimilars to include thesenew biosimilars and has producedseparate guidance for specictherapy classes, includingmonoclonal antibodies.

The biologic medicines marketis expected to grow to $190-200billion by 2015, with biosimilarsa small but growing proportion at$2-2.5 billion. (17)

Unlike the development of genericmedicines, biosimilar manufacturersare expected to need to invest inclinical trials, manufacturing and

post-approval safety monitoringprograms similar to that of theoriginal innovator companies.

According to Sandoz, the cost ofdeveloping a generic small moleculeis around $2-3 million, whereas

biosimilars have been estimated tocost around $75-250 million to reachapproval, (18)largely due to the theexpected number of clinical studiesand analyses.

Because of this investment, cost

savings achievable with biosimilarsmay not be as great as can beexperienced with small moleculegenerics. (12)

The cost ofdeveloping biosimilars



R e g ul a t i n

g b i o s i mi l ar s Regulating

biosimilars



“The approach established for generic medicines

is not suitable for development, evaluation andlicensing of similar biotherapeutic products(SBPs) since biotherapeutics consist of relativelylarge and complex proteins that are difcultto characterize”. (8)

The World Health Organization

Regulatingbiosimilars



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Regulatingbiosimilars

In 2009 the World Health Organization developed a set of globally acceptedstandards to assure the safety, efcacy and quality of biosimilar medicines.These have been developed in the wake of increased interest in biosimilarsby local regulatory authorities seeking to develop national standards. (8) (25)

Reference productThe reference product should be authorized in the country or region in question

QualityAll aspects of quality and heterogeneity should be assessed includinghead-to-head comparisons with the reference product

Non-clinical dataShould include pharmacodynamic, pharmacokinetic and comparative repeat-dosetoxicity studies in a relevant species

Clinical studiesRequired to demonstrate similar safety and efcacy. Immunogenicity shouldalways be investigated in humans before authorization

Pharmacovigilance and risk managementA pharmacovigilance plan is required when an application is submitted and a riskmanagement plan may be necessary in some cases

World Health Organization (WHO) guidance on biosimilar development standards (25)



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Approval pathways forbiologic and biosimilarmedicines

Before marketing authorization isgranted by regulators such as theU.S. Food and Drug Administration(FDA) or the European MedicinesAgency (EMA)/EuropeanCommission (EC), originatorcompanies and biosimilarmanufacturers must submit robust

data to demonstrate a product’sefcacy and safety prole. Extensiveanalytical chemistry, manufacturingand control (CMC), non-clinicaland clinical evidence will likely berequired for the relevant therapeuticarea. (7) (26)

The approval pathway for abiosimilar medicine may beabridged in comparison to theoriginator product. Where thereare approval pathways, in orderto gain approval as a biosimilar,the manufacturer must providesubstantial data to show that itsproduct is sufciently similar tothe original product. Specically,the biosimilar must demonstratethat it has no signicant clinicaldifferences to the referenceproduct, but some limited variationis permitted. This is becausebiosimilar approval is based ona demonstration of similarity to

a previously approved originatorproduct rather than ade novo demonstration of safety andeffectiveness (7) (8)

A decision on how extensiveclinical data need to be dependson each individual case. However,the amount of clinical efcacyand safety data will be less fora biosimilar than the originalbiologic. (27)

The 2012 draft FDA biosimilarguidance provides a list of factorsthat a sponsor should considerwhen assessing the similarity of its

proposed products including:• Expression system

• Manufacturing process

• Physicochemical properties

• Functional activities

• Receptor binding and

immunochemical properties• Impurities

• Characterization of the referenceproduct and reference standards

• Characterization of the nisheddrug product

• Stability (10)



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Not to scale. Comparison of originator and biosimilar marketing approvals process in the US and EU(28) (29)

Due to the varied nature ofbiotechnology products and theirpotential risks, manufacturers

of both biologic medicines and

Analytical

Quality

Non clinical

Clinical

Clinical Non clinical

Non clinical

Clinical Pharm Clinical Pharm

Clinical S&E Clinical S&E

Originator

Originator

United States

European Union

Biosimilar

Biosimilar

Non clinical

Comparability data

Analytical

Quality

biosimilars are required to submitpharmacovigilance and riskmanagement plans as part of their

application. (8) (30)

Cross reference

Cross reference

(extrapolation?)



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Europe

• The European Medicines Agency (EMA)/European Commission (EC)was the rst major regulatory authority to implement a framework for themarketing authorization of biosimilars and has one of the most detailedand stringent guidelines for developing biosimilars.

• The guidelines outline an approach for comparing the proposed biosimilarto the original biologic, covering quality, consistency, manufacturingprocess, safety and efcacy. (7)

• Product-speci c guidelines for biologic medicines, eg: recombinanterythropoietin, are provided by the EMA/Committee for MedicinalProducts for Human Use (CHMP), outlining the data requirements andstudies necessary to demonstrate comparability.

• The EMA/CHMP guidelines are widely considered the gold standard, withcountries such as Australia, Canada, Japan, Korea and South Africa usingthem as a basis for their own regulations. (31) (32)

Guiding the way for biosimilars development



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United States

• In March 2010, the U.S. biosimilar pathway was signed into law aspart of the Affordable Care Act. In February 2012, the Food and DrugAdministration (FDA) issued three draft guidance documents on biosimilarproduct development to assist industry in developing such products in theUnited States. What, if any, additional guidance FDA may issue, and when,is uncertain. (26)

• The FDA recommends a stepwise approach to demonstrate biosimilaritybetween a proposed medicine and the original biologic. The aim is todemonstrate no clinically meaningful difference in terms of safety, potencyand purity. The guidance provides advice on the types of rigorous studiesthat should be undertaken by the manufacturer to address uncertaintyabout the proposed product.

• To comply with this approach, a sponsor should include:

» Structural analysis: Using state-of-the-art technology to display,for example, primary and higher order structures, post-translationalmodications, and intentional chemical modications.

» Functional assays: Appropriate studies including: bioassays,biological assays, binding assays and enzyme kinetics. FDArecommends that any functional assays performed should becomparative “so they can provide evidence of similarity, or revealdifferences...”

» Animal data: Including toxicity studies, pharmacokinetic andpharmacodynamic measurements, and immunogenicity studies.

» Human clinical studies: Including pharmacokinetic andpharmacodynamic measurements, immunogenicity results, and safetyand efcacy data. Studies should demonstrate that the proposedproduct has neither decreased nor increased activity compared to thereference product.

» The FDA has discretion to waive any requirement deemed unnecessary. (26)



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Biosimilar regulationsWithin the European Union,Member States are generallyresponsible for implementingregulation adopted at EU level;governing the development,authorization and manufacturing ofbiotherapeutics. The EMA was therst to create biosimilar guidelinesin 2005, swiftly followed by therst approved biosimilar productsin 2006. Today, 13 biosimilarproducts have been approved bythe EMA. (17)

Regulation has evolved rapidlywith many countries establishingnational guidelines based on theWHO and EMA/EC framework.Guidelines are helping to openup the development and approvalof biosimilars worldwide, butdenitions and terminology forbiosimilarity vary, as does guidanceon the original reference product forcomparability studies and the scopeof data required for marketingapproval. (31)

Biosimilars are a relativelynew, emerging market.Regulatory guidelinesand standards are stillbeing developed in somecountries and they areconstantly evolving astechnology develops.

2000 2001 2002 2003

EULegal

Pathway

EUOverarchingGuidelines

Guideline development

2004 2005 2006

AUS

The EMA published the firstbiosimilar regulatory approvalpathway for the EU member states

As more governments develop biosimilarpathways, the WHO and EU’s establishedguidelines will continue to serve as a

template, as demonstrated by Australia’sunadulterated adoption of the EU guidelines



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TUR

MYS

2007 2008 2009 2010 2011 2012

TWN

KOR

JPN

SIN

WHO

CAN

ZAF

BRA

SAU

MEX

CUB

IRI

IND

PER

USA(draft)

COL(draft)

JOR(draft)

THA(draft)

ARG

The WHO biosimilar guideline, aimed at

providing a consistent scientific standard,is the model for many newly developedbiosimilar pathways

Some emerging markets have developed their own regulatory pathwaysfor biosimilars, hoping to meet a growing demand for biologic medicines.Singapore and Malaysia amended their guidelines mainly in accordancewith the EMA guidelines, while Brazil and Cuba chose the WHO andCanadian guidelines as the basis for developing regulations. (31) Indiareleased ofcial guidelines in June 2012(33), before which around 20

biosimilars were approved for use within India under an ad hoc abbreviatedprocess. (34) The WHO will continue to monitor progress.

Biosimilar Regulations Global guideline/regulation development



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P h ar m a c ov i gi l an c e

an d t r a c e a b i l i t y

Pharmacovigilance and traceability



“It should be recognized that, by denition,similar biological medicinal products are notgeneric medicinal products, since it could beexpected that there may be subtle differencesbetween similar biological medicinal productsfrom different manufacturers or compared withreference products, which may not be fullyapparent until greater experience in their use hasbeen established. Therefore, in order to support

pharmacovigilance monitoring, the specicmedicinal product given to the patient should beclearly identied.” (36)

The European Medicines Agency

Pharmacovigilance

a n d t r a c e a b i l i t y



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An important concern with allbiologic medicines is the risk of anunwanted immune response, wherethe patient reacts against proteinsin the medicine, limiting its efcacyor affecting its safety. (30) Rigorouspharmacovigilance programs areneeded to protect patients and ensureany adverse events are quicklydetected, reported and attributed tothe correct product and manufacturer.

Safety monitoring and ongoingpharmacovigilance of medicinesinvolves detection, assessment,

understanding and prevention ofadverse effects. As clinical trialsinvolve a relatively small numberof patients, potential reactions maybe unknown at the time of launch. (8) As with all medicines, the safetyof biosimilars is monitored postmarketing to assess and identify any

long-term or rare adverse events.

In Europe and the U.S., it isobligatory for the manufacturers ofall biologic medicines to submitcomprehensive pharmacovigilanceand risk management plans whenapplying for approval. Potentialpharmacoviligance programsmay be a greater considerationfor biosimilars, where the clinicalsafety and efcacy package is likelyto be more limited at launch thanthat of the original biologic. (11)

Risk management and post-marketingpharmacovigilance considerations

should include:

• Pre and post-authorizationcomparative testing

• Regular tests to ensure that themanufacturing processes are thesame, as biosimilarity and immu-nogenicity are dependent on this

• Risk management in case ofadverse drug reactions (35)

Pharmacovigilance and traceability

Connecting worldwide adverse event reportingThe WHO Program for International Drug Monitoring is based on the principle of internationalcollaboration in the eld of pharmacovigilance. Over 100 member nations have systems in placethat encourage healthcare professionals to record and report adverse drug reactions in their patients.These reports are assessed locally and may lead to action within the country. Through membershipof the WHO program, one country can know if similar reports are being made elsewhere. (37)



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Naming, trackingand tracing medicinesThe ability to track and trace all

biologic medicines and biosimilarsthroughout the product lifecycle iscritical to protecting patient safety.Physicians need accurate data onadverse events linked to treatmentsto ensure they are prescribing safeand effective medicines to patients.

Currently, the InternationalNon-proprietary Name (INN) for anew biosimilar may be the sameas that of the original biologicmedicine. In such a case, if onlythe INN, without a distinguishablename, is used when prescribinga biologic medicine, the treatingphysician may not know preciselywhich medicine a pharmacist gavethe patient.

Without distinguishable INNs,a reporter may be unable toimmediately identify whichmedicine was given when a patient

experiences an adverse event.It could then be unclear whatmedicine caused the adverse event,which may lead to inappropriatelabeling of a class effect for all

biologic medicines with the sameINN and a delay in establishing theroot cause of the problem. (38)

Regulations are being tightenedto improve identication andtraceability of biologic medicines.In 2012, the European Commission

introduced a pharmacovigilancedirective, which was the biggestchange to the regulation of humanmedicines in Europe since 1995.It is now a legal requirement forEU Member States to take allnecessary measures to clearlyidentify the biological medicinesthat are prescribed, dispensedand sold in their country. MemberStates are empowered to imposethese requirements on doctors,pharmacists and other healthcareprofessionals. (39) A similar namingprogram is recommended by theWHO and national regulatorybodies, such as the UK’s Medicinesand Healthcare products RegulatoryAgency (MHRA). (40)



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In the U.S., recent decisions bythe FDA embody a patient safety-focused approach to naming

biologic medicines. Although theFDA has expressed that this namingapproach should not be taken as anaming convention to be applied tobiosimilars, there is recognition ofthe need for clear naming principlesfor biologic medicines. Two recentbiologics approved through the

FDA’s 351(a) BLA pathway requiredunique, non-proprietary namesby adding a prex with a hyphen:ziv-aibercept (Zaltrap®) and tbo-lgrastim (trade name TBD). Thesebiologics are related to previouslyapproved products – Regeneron’sEylea® (aibercept) and

Amgen’s Neupogen®

(lgrastim)respectively. (41) (42)

The FDA concluded that thenon-proprietary names for ziv-aibercept and tbo-lgrastimshould be different to their

reference biologics, to avoidpatients receiving the incorrectproduct and to reduce confusionamong healthcare providers whomay perceive them to be clinicallythe same, because they have thesame non-proprietary name.(41)

The FDA has also made thebroader conclusion that the use ofdistinguishable non-proprietarynames will help post-marketingsafety monitoring, allowing bettertraceability of medicines in the caseof an adverse event. In addition,the use of brand names alonewas determined to be insufcientas brand names are often notused by healthcare professionalsfor prescribing, and manypharmacovigilance systems do notrequire them.(41)

Amgen – who develops both originator and biosimilar medicines –believes prompt identication and resolution of product problems canbe enabled by distinguishable, non-proprietary names. This would help:

• Facilitate prompt identi cation and resolution of product problems• Facilitate manufacturer accountability

• Avoid incorrectly implying that the molecules are identical



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S u b s t i t u t i on an d

i n t e r c h an g e a b i l i t y

Substitution and interchangeability



Substitutionand

i n t e r c h a n g e a b i l i t y



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Substitution and interchangeability

Most generics are consideredto be therapeutically equivalent(or interchangeable) with theirreference products (43), meaningthe effects of both drugs areexpected to be identical and thatconsequently it doesn’t matterwhich drug the patient receivesat any time. (13) In the U.S. drugsthat are interchangeable are givenan AB-rating by the FDA. (44) Bycontrast, although biosimilars aresimilar to their reference products,they are not clinically identical andthere is scope for differences ineffects in patients. (12)

Substitution (sometimes calledautomatic substitution ) is often

permitted for generics that areconsidered to be interchangeableor clinically identical. Thepracticalities of substitutionvary from country to country.In some countries, the doctor

is encouraged to prescribesubstitutable medicines by INN,leaving the pharmacist to decidewhich brand (generic or referenceproduct) to dispense, whereas inother countries the pharmacistmay dispense a generic of asubstitutable medicine even wherethe doctor has prescribed thereference product by brand. (38)

In all cases, however, the essentialfeatures of substitution are that:

• it is the pharmacist (and not thedoctor) who decides which brandthe patient receives;

• the doctor is not routinelyinformed of which brand thepatient has received;

• the patient may potentially receivea different brand every time theirmedicine is dispensed.



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Because generic medicines aretherapeutically equivalent with theirreference products, substitutiondoes not usually have any negativeimpact on the patient or on publichealth. (13) However, biosimilarsare not clinically identical to theirreference products so substitutionof biosimilars and their relatedbiological products can result inproblems, such as:

• A lack of traceability in the case ofan adverse event. If substitutionhas taken place, the doctor maynot know which brand was usedand so only the INN can beincluded in the adverse eventreport. This lack of traceabilitymay prevent identication of theparticular product responsible forthe adverse reaction. (12)

• Confusion in tracing the cause ofa delayed adverse event. Someadverse reactions, including manyimmunogenic reactions such aspure red cell aplasia (PRCA), aredelayed in onset and may develop

only after several months oftreatment. (45) (46) With substitutionand frequent switching betweenproducts, a patient may receiveseveral different products prior toan immunogenic reaction.

This makes tracing the medicineresponsible for the reaction verydifcult, even when each differentproduct can be identied bybrand. (13)

Regulatory authorities recognizethe risks of substitution for biologicmedicines, and in Europe the EMAstates that for questions relatedto switching from one biologicmedicine to another, patientsshould speak to their doctor andpharmacist. (9)

Across the EU, decisions onprescribing practices such as

substitution are made at nationallevel. In many countries (eg: Italy,France and Germany), biologicmedicines are specically excludedfrom lists of products suitablefor substitution (15), whereas inother countries where substitutionis permitted only for INN-only

prescriptions (eg: Sweden andUK) doctors routinely prescribebiologics by brand.



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Substitution and interchangeability at a glance

U.S. – FDAThe FDA can designate a biosimilar as an interchangeable biologicwhen the following criteria are met:

Europe – EMADecisions on substitution are made at national level. In many EUcountries, automatic substitution of biologics is ofcially prohibitedor not recommended. (9)

WHOThe WHO does not dene standards on interchangeability for biologicmedicines. It recognizes that a number of issues associated with theuse of biologics should be dened by the national authorities. (8)

1. The biologic product isbiosimilar to the reference biologicproduct; and

2. It can be expected to producethe same clinical results as thereference productin any given patient ; and

3. for a biological product that is administered more than once toan individual, the risk in terms of safety or diminished efcacyof alternating or switching between use of the biological product

and the reference product is not greater than the risk of using thereference product without such alternation or switch.(47)



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The variation in global substitution guidelines

Canada does notsupport automaticsubstitution (25)



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As the biosimilar market expands and biosimilarsbecome more complex, it is important to ensureclarity in prescribing regulations.

UK andBelgium recommendprescribing by brand

name to avoidsubstitution (15)

Spain,Germany and

France prohibit

automaticsubstitution (15)

Ireland,Poland and

Portugal have noclear position (48)

In Japan,substitution should

be avoided during thepost-marketing

surveillance period (25)



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M an uf a c t ur i n

g

b i o s i mi l ar s

Manufacturing biologics



A biologic medicine typically has around250 in-process tests during manufacturing,compared with around 50 tests for a smallmolecule, to demonstrate safety and equivalentefcacy and to ensure safe, reliable productionof therapies for patients. (13)

Manufacturing

b i o s i m i l a r s



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Manufacturing biologics

Transforming complex therapeuticproteins from the laboratory intothe large-scale production of safeand effective medicines requireshighly specialized knowledge,processes, scientic standardsand quality systems. The challengein manufacturing either biologicor biosimilar medicines is tocontrol variability in this processto ensure compliance with quality

standards so that every patient canbe treated with a consistently safeand effective medicine, every time.Where necessary, regulatory bodiesmay require additional pre-clinicaland/or clinical data in order todemonstrate that the manufacturingprocess does not impact theefcacy or safety of the product.



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Good manufacturing practice for largemolecules and small molecule medicines

Purificationmultiple steps

Remove impuritiesHighly selective resinSpecific process conditions

Large molecule

Process GMP requirements(Good Manufacturing Practice)

STEP 1

STEP 2

STEP 3

STEP 4

STEP 5

STEP 6

STEP 7

STEP 8

STEP 9

STEP 10

STEP 11

Harvest Remove cells from product

Cell culture Bioreactor media pH, temperature

Cell expansion

Cell line developmentDNA - CloningTransfectionSelect "best" cell

Finishing LyophilizationSyringe-fill

Packaging & storageControlled temperatureEnsure no foamingNo particles

Quality assurance& characterization

Highly precise methodsReference standards

Stability Testing to ensure productremains stable through shelf life

Filling Filling methodNo human contact

Virus inactivation/removal Dedicated steps to ensure viruskilling or reduction

Biologics have more GMP-requirements than small molecules

Media pH, temp cell density



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GMP requirements(Good Manufacturing Practice)

Small molecule

STEP 1

STEP 2

STEP 3

STEP 4

STEP 5

STEP 6

STEP 7

Room temperature

Process

Good Manufacturing Practice (GMP)Clean room & sterile equipment (prevention and control of potential bacterial contamination)

Virus segregation (prevention of potential virus contamination)

Segregation: Personnel and material

Compress (solid dosage)Filling (liquid dosage)

Packaging & storage

Quality assurance& characterization

Stability

PressureFilling method(no human contact)

Mix Mixing speed, time

Weigh Weigh API& inactive chemicals

ReactionAdd ingredientspressure, temperaure

Testing to ensureproduct remains stablethrough shelf life

Easy methods

To manufacturesafe and effectivebiologic and biosimilarmedicines, more stepsand more stringentprocesses for eachstep are required than

for small moleculemedicines.

Much like the way in which varieties of wine have common characteristicsbut may vary in quality and taste depending upon region, vineyard, growingconditions and so on, the characteristics of a protein may vary dependingupon the manufacturing process, including the growing conditions, forthe protein. This sensitivity to environmental factors in production isan inherent and important difference between biologic medicines andtraditional, chemical medicines.



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The manufacturingprocess is unique to every

manufacturerThere is a strong relationshipbetween the manufacturingprocesses of a biologic medicineand the characteristics of thenal product. Due to proprietaryknowledge, it is impossiblefor biosimilar manufacturers

to precisely replicate themanufacturing process of theoriginal biologic or the activeingredient of the protein product. (49)

The starting materials for mostbiologic medicines are genetically-modied cells. Once scientistsdesign and select a cell thatproduces a medically valuableprotein, they replicate it to create acell line. Each cell line is unique tothe manufacturer.

The major steps involved withthe manufacture of biologicmedicines include:

• Modifying the selected cell

• Growing a cell line from theoriginal modied cell

• Growing a large number of

cells from the cell line

• Cultivating them to producethe desired protein

• Separating the protein fromthe cells, and

• Purifying the collected protein

Cell expansion

Unit Operation

Cell production in bioreactors

Recover through filtration orcentrifugation

Purification through

chromatopgraphy

Characterisation and stabilityPurified bulk drug



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Striving to ensure aconsistent supplyProblems or interruptions to the

manufacturing process of biologicmedicines may not only affectquality and safety, but could alsolead to delayed supplies anddistribution of urgently neededmedicines.

Along with regulators,

manufacturers have a responsibilityto ensure strategies are in placeto minimize incidences of drugshortages and possible disruption.Manufacturer risk management isa continuous and holistic processdesigned to ensure a consistentsupply. Strong governance canalso help to integrate and managesupply risk across manufacturingplants and functions.



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G l o s s ar y

Glossary



Glossary



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Biologic License Application (BLA): An application submitted to the FDA seekingapproval to market a biologic in the United States. The application contains a description ofthe trials and results, formulation, dosage, drug shelf life, manufacturing protocols, packaging

information, etc. There are two different types of BLAs: full, stand-alone BLAs led forapproval of an originator biological product, and abbreviated BLAs led for approval of abiosimilar product.

Biosimilar: Dening biosimilars

THE WORLD HEALTH ORGANIZATION: “A biotherapeutic product which is similar in terms ofquality, safety and efcacy to an already licensed reference biotherapeutic product.” (8)

THE EUROPEAN MEDICINES AGENCY: A biological medicine that is developed to be similar toan existing biological medicine (the ‘reference medicine’). When approved, a biosimilar’svariability and any differences between it and its reference medicine will have been shown notto affect safety or effectiveness. (9)

THE U.S. FOOD AND DRUG ADMINISTRATION: A biological product that is highly similar to aU.S. licensed reference biological product notwithstanding minor differences in clinicallyinactive components, and for which there are no clinically meaningful differences between thebiological product and the reference product in terms of the safety, purity and potency of theproduct. (10)

Biotechnology: Technology based on biology, especially when used in agriculture, foodscience and medicine. The United Nations Convention on Biological Diversity denesbiotechnology as “any technological application that uses biological systems, livingorganisms, or derivatives thereof, to make or modify products or processes for specic use”.

The Center for Drug Evaluation and Research (CDER): As part of the US Foodand Drug Administration (FDA), CDER regulates over-the-counter and prescription drugs,including biologic therapeutics and generic drugs.

Chemical drug or chemical medicine: Refers to medicines that are manufactured withoutthe involvement of living organisms.



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Chemistry, manufacturing and control (CMC): The CMC stage of product developmentfocuses on how a drug was created. It should be demonstrated that the manufacturingmethod is proper and valid on a technological level and that quality is ensured through

consistent production in accordance with the WHO’s Good Manufacturing Procedure. Manyaspects of both the active ingredients and the product as a whole will be reviewed, includingcharacterization, control and stability.

Clinical trial: A test in which a drug or biologic is given to humans to establish how it worksin the body and measure the nature and extent of any intended or unintended consequences.

Committee for Medicinal Products for Human Use (CHMP): The CHMP is the

scientic committee responsible for formulating the opinion of the European Medicines Agencyon any question concerning the evaluation of human medicinal products.

Comparability exercise: The head-to-head comparison of a biotherapeutic product witha licensed originator product, with the goal of establishing similarity in quality, safety, andef cacy. Products should be compared in the same study using the same procedures.

Data exclusivity: The period of time during which the clinical testing data that supportedapproval of the innovator medicine is protected, so that the prior approval of that originatorbased on those data may not be relied upon by another applicant to help approve a copy ofthat product.

DNA (Deoxyribonucleic Acid): DNA is a nucleic acid that contains the genetic informationused in the development and functioning of all cellular organisms. Molecular systems interpretthe sequence of these nucleic acids to produce proteins.

Efcacy: The desired impact that a medicine or treatment has when administered to a human.

European Medicines Agency (EMA): The EMA is responsible for evaluating marketingapplications for medicinal products to be approved in the European Union.

Federal Food, Drug and Cosmetic Act: The federal law that regulates FDA’s licensing ofdrugs but not the majority of biologic medicines. Instead, most biologic medicines are licensed

by FDA under the Public Health Service Act. Once licensed by FDA, however, most of the other



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provisions set forth in the Federal Food, Drug and Cosmetic Act concerning the marketing andother regulatory requirements are applicable to both drugs and biologic medicines.

U.S. Food and Drug Administration (FDA): The federal agency responsible forevaluating marketing applications and/or otherwise regulating the U.S. marketing of medicinalproducts, medical devices, food and cosmetics to be approved in the United States.

Fusion protein: A protein made from a fusion gene, which is created by joining parts of twodifferent genes. Fusion genes may occur naturally in the body by transfer of DNA betweenchromosomes.

Generic medicine: A generic drug is the same as a brand name drug in dosage, safety,strength, how it is taken, quality, performance, and intended use. A generic drug product mustcontain the identical amounts of the same active ingredient(s) as the brand name product.Drug products evaluated as “therapeutically equivalent” can be expected to have equal effectand no difference when substituted for the brand name product.

Genetic engineering: The direct manipulation of an organism’s genes by introducing,eliminating or rearranging specic genes using the methods of modern molecular biology,particularly those techniques referred to as recombinant DNA techniques. These techniquesentail producing a piece of DNA (the recombinant DNA or synthetic rDNA construct) andintroducing it into an organism so that new or altered traits can be imparted to that organism.

Guidance: A document issued by a regulatory agency to provide interpretation of a law thatthe regulatory agency is responsible for administering and/or enforcing and recommendationsas to how to proceed with particular issues.

Immune system: The collection of mechanisms within the body that protect against diseaseby identifying and attacking foreign substances in the body.

Immunogenicity: The ability of a substance to trigger an immune response or reaction (eg:development of specic antibodies, T-cell response, allergic or anaphylactic reaction).

INN (International non-proprietary name): Allocated by the World Health Organization,

an INN identies pharmaceutical substances or active pharmaceutical ingredients. Each INN



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is a unique name that is globally recognized and is public property. A non-proprietary name isalso known as a generic name.

Innovator: Describes a company that invested considerably in research and development todevelop a new medicine through innovative technologies, such as biotechnology.

Innovator product: Original approved biologic medicine.

Insulin: A hormone that affects metabolism and causes the body’s cells to take up glucose(sugar) from the blood and store it as glycogen in the liver and muscles.

Interchangeability: Where two products, that are judged to be similar, can be exchanged onewith another without a signicant risk of an adverse health outcome.

Large molecule drugs: Are therapeutic proteins – also known as biologic medicines.Essentially, these are copies or optimized versions of endogenous human proteins.

Mechanism of action: The specic way by which a medicine achieves the desired outcome.

Medicines and Healthcare products Regulatory Agency (MHRA): UK governmentagency that is responsible for ensuring that medicines and medical devices work and areacceptably safe.

Monoclonal antibody: An antibody produced in the laboratory by a single clone of cells or acell line and consisting of identical antibody molecules.

Originator: See above for innovator.

Originator product: See above for innovator product.

Pharmaceutical medicine: Also referred to as medicine or medication – any chemicalsubstance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.

Pharmacodynamics: Studies performed to determine what a drug does to the body.



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Pharmacokinetics: Studies performed to determine what the body does to a drug.

Pharmacovigilance: Procedures that monitor the safety of medicines to detect, assess,

understand, and prevent adverse effects or any other safety-related issue.

Preclinical trials (or studies): Tests that take place in a scientically-controlled settingusing cell culture and/or animals as disease models.

Proteins: Compounds (chains of amino acids) constituting the ultimate expression product ofa gene. Created through the synthesis performed by ribosomes, proteins are the workhorses ofliving systems, causing chemical processes and changing as their environment changes.

Recombinant: In genetics, recombinant means DNA, proteins, cells, or organisms that aremade by combining genetic material from two different sources. Recombinant substances aremade in living cells and are being studied in the treatment of cancer and for many other uses.

Reference product: The innovator/originator product that the biosimilar product is intendedto copy.

RNA: Ribonucleic acid is a nucleic acid which is central to the synthesis of proteins.

Similar biotherapeutic product (SBP): A biotherapeutic product which is similar in termsof quality, safety and efcacy to an already-licensed, reference biotherapeutic product.

Small molecule drugs: Chemical compounds that have a dened structure andcharacteristics.

Switching: The decision of a physician to change a patient from one drug to another drugwith the same therapeutic intent, in order to optimise therapy and reduce adverse effects.

Vaccine: A biological preparation which is used to establish or improve immunity to aparticular disease.



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biologics and biosimilars overview

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