Pharma Bio World April 2013 27India can Emerge as a Key Player in theBiosimilar SegmentBiosimilar, which are new versionsof innovator biopharmaceuticalproducts that are marketed afterexpiration of patents, have emerged asone of the fastest growing developmentopportunities in the biopharmaceuticalsector. Regulatory agencies evaluatebiosimilars based on their level ofsimilarity to, rather than the exactreplication of, the innovator drug. Theneed for increased analytics and thedesire for compressed timelines inbiosimilars development demands inparticular that developers must investearly in Chemistry, Manufacturing,and Controls (CMC) type analysisto demonstrate comparability to thereference molecule at every stage,particularly during manufacturing. Whileconventional generics are expected toface competition and pricing pressuresin most developed markets, Indianpharmaceutical companies have alreadystarted gearing up for the next big thing —biosimilars. These are generic versionsof biological medicines that depend onthe same mechanism of action, and areused for the same therapeutic indication,as the innovator product.Recognising the opportunity, India hasalready taken its first step forward totap the emerging opportunity in thebiosimilars’ space. While almost allmajor Indian drug makers have outlinedplans, identified products and set asideinvestment budgets to develop a robustproduct pipeline, some have evenstarted rolling them into the market. Forinstance, Dr Reddy’s Laboratories hasThe biosimilars industryhas been growingstupendously. In the lastfew years, India has seena robust growth in itsbiosimilars portfolio. Thisarticle aims to identify andanalyse the biosimilarsmarket and the regulatoryscenario in India.already launched a few of its significantbiosimilars in emerging markets. Onthe other hand, companies like Ciplaare making huge investments in Indiaand outside to acquire manufacturingfacilities and potential product pipelinesin the biosimilar segment. The companyhas not only acquired facilities in Indiaand China to develop biosimilars, morerecently, it has also rejigged some of itsinvestments in China to divert more fundstowards biosimilars. Similarly, Wockhardtand Lupin have made their foray into theniche segment.Development ChallengesSimilar biologics are developed throughsequential process to demonstrate thesimilarity by extensive characterisationstudies revealing the molecular andquality attributes with regard to thereference biologic. Biosimilars mustbe systematically engineered to matchthe reference product. A comparabilityexercise must be followed with theinnovator product at all levels of productdevelopment, including: physicochemicalattributes, biological activity, preclinical invivo comparability, Phase I PK and safety,and Phase III efficacy and safety.This can be difficult because data for theinnovator product will be lacking. Theonly way to get information about thecomponents of the innovator product isfrom material that is already out in themarketplace. Having multiple batchesof the innovator’s product, spanning anumber of years, can be extremely helpfulJ RamniwasFounder & CEOSai Pharma Solutions Inc, Vadodara““Biosimilars are generic versions of biologicalmedicines that depend on the same mechanismof action, and are used for the same therapeuticindication, as the innovator product.
Pharma Bio World28 April 2013during the characterisation process.Sources of variation between manufactureof innovator biopharmaceutical andbiosimilar are as given below:• Use of different vector• Different cell expression system• Different cell line growth media andmethod of expansion• Different operating conditions• Different binding and elution conditions• Different methods, reagents,reference standardsManufacturing Process ofBiopharmaceuticalsThe manufacturing process for similarbiologic should be highly consistentand robust. If the host cell line usedfor the production of reference biologicis disclosed, it is desired to usethe same cell line as the referencebiologic. Alternatively any cell linethat is adequately characterised andappropriate for intended use can beused to develop a similar biologic, withprocess- and product-related impurities,the relevant immunochemical properties,and results from accelerated degradationstudies and studies under variousstress conditions.In order to demonstrate that you havea similar product, you need to haveyour analytical assays in place duringthe process of development. Theseassays will help to best replicatewhat the innovator has done. Overall,the characterisation you need to dofor a biosimilar will always be muchhigher than that for a new biologicalentity (NBE).The analytical characterisation of abiosimilar should include primary,secondary, tertiary, and quaternarystructural assessment, biological activity,and analysis of product and processimpurities.All of these components must beunderstood and characterised during yourcomparability studies of the biosimilar tothe innovator product.appropriate justification in order tominimise the potential for significantchanges in critical quality attributes ofthe product and to avoid introduction ofcertain types of process related impuritiesthat could impact clinical outcomesand immunogenicity.The data requirements for review ofmanufacturing process at preclinicalsubmission stage include a completedescription of the manufacturing processfrom development and characterisationof cell banks, stability of clone, cellculture/fermentation, harvest, excipients,formulation, purification, primarypackaging interactions (if different fromreference biologic), etc.Analytical Characterisation of BiosimilarsThorough characterisation andcomparability exercise are required, anddetails should be provided on primary andhigher-order structure, post-translationalmodifications, biological activity,Closing ofspecific genesequence intoviral or non-viralvectorTransfer intohost cell forexpressionCell expansionProteinProductionProteinrecoverythroughfiltration ¢rifugationProteinPurification bychormatographyProteincharacterization& stabilityUse of differentvectorDifferent cellexpressionsystemDifferentcelline growthmedia &method ofexpansionDifferentoperatingconditionDifferentbinding& elutionconditionsDifferentmethodsreagents,referencestandardsBiopharmaceutical ManufacturingSources of variation between manufacturing of innovator biopharmaceuticals and biosimilarsFigure 1 : Variation bitween Manufacturing of biopharmaceuticals and biosimilars
Pharma Bio World April 2013 29Regulatory Issues of Concern for theUse of BiosimilarsIn order to make foray in to the globalregulated markets, Indian manufactureswill have to resolve the following issues onthe priority basis due to different sourcesof variations between manufactureof innovator biopharmaceutical andmanufacture of biosimilars:1. Quality Issues2. Efficacy Issues3. Safety Issues4. Pharmacovigilance5. Substitution6. Naming and Labeling7. Regulatory ApprovalRegulatory Landscape in IndiaDue to the complexity of biologics, aproduct can only be made that is similarto the innovator drug, not identical.Basically, it’s impossible for two differentmanufacturers to produce two identicalproducts even identical host expressionsystems, processes, and equivalenttechnologies are used. Therefore, wehave to rely on analytics to compare thebiosimilar to the innovator product onthe market.Advances in current state-of-the-art analytical methods enhance thelikelihood that a product will be highlysimilar to another product throughbetter targeting of the original product’sphysicochemical and functionalproperties. Sponsors with compellingcomparability data observe a reducedregulatory burden.The Department of Biotechnology, alongwith the drug regulator (CDSCO), hasalso got into action and has floatedguidelines in 2012” Guideline on similarbiologics: Regulatory RequirementsMarketing Authorisation in India “forbiosimilar drugs. The proposed normsoutline specific requirements forpre-marketing and post-marketing data,apart from guidelines for pre-clinical andclinical trials for biosimilars.The move is aimed at upgrading andmaintaining the quality of biosimilarproducts that are manufactured in India. Inthe development of these guidelines, thedepartment of biotechnology and the drugregulator (CDSCO) have given referencesof ICH guidelines so that productsdeveloped and imported in India will beper the global regulatory standards so thatthe Indian manufactures can leverage thetechnological advantage to manufacturingquality, safe and effective products.Regulatory applications and approvalsissued at different stages of biosimilarsproduct development in India are shownin Figure 2.SrNoStage of development ormanufacturingRegulatoryAgency involvedApplicationformatApprovalformat1. Manufacturing License for test,analysis and examinationState FDA /CDSCOForm 30 Form 292. Preclinical studies permission RCGM Form C3 Form C43. Submission of Preclinical study report RCGM Form C5 Form C64. Clinical Trial CDSCO Form 44 Permissionletter5. Manufacturing and MarketingpermissionCDSCO Form 44 Form 46A(Bulkproduct)Form 45/46(Finishedproduct)6 Form 46A (Bulk product)7. Commercial Manufacturing License State FDA /CDSCOForm 27 D Form 28 D8. Registration and Import License CDSCO Form 40/Form 8Form 41/Form 10traditional prescription drug, the productmust have the same active ingredient,strength, dosage form and route ofadministration as the original drug. Thismeans that generic drugs are the exactsame chemically as their brand namecounterparts and they act the same wayin the body.Such a process is not possible withbiologics. Biologics manufacturers mustensure that the manufacturing processremains the same over time by tightlycontrolling the source and nature ofstarting materials and consistentlyemploying hundreds of process controlsthat guarantee predictable results. WhenThe applicant should comply with theestablished pharmacopoeia requirementswhile testing the excipients and as well asbiological product for which monographis available in Indian Pharmacopoeia.Challenge of Manufacturing Biosimilars:For a generic drug manufacturer towin approval of a generic version of aa biosimilar is created, it requires a newmanufacturing process with new startingmaterials. As a result, it will produce aproduct that is different from and nottherapeutically equivalent with that of thebrand name biologic.For new entrants, biosimilarspose very different challenges toFigure 2: Various application forms for submitting request to regulatory agencies
Pharma Bio World30 April 2013Contact : firstname.lastname@example.org presented by small moleculegenerics, with more demandingrequirements in terms of :• Sophisticated technologies• Clinical development, clinical trialexpertise and proving bioequivalence• Market access• Manufacturingindedicatedmanufacturingfacility• Sales and marketing capabilitiesBecause of the complex process ofmanufacturing biologics, the onlyway to establish whether there aredifferences that affect the safety andeffectiveness of the biosimilars is toconduct clinical trials on each newproduct. The human body is moresensitive than any laboratory test andthat’s why these tests are necessaryto determine if biosimilars have anyadverse impact in humans.Advantage to Manufacturing BiosimilarsThe “Guideline on similar biologics:Regulatory Requirements MarketingAuthorisation in India” have beendeveloped by taking the internationalregulatory standards in to considerationso that Indian manufactures canmanufacture the biosimilars as perglobal GMP regulations and canmake foray in to the world marketslike US, Europe, Japan etc withmore confidence beating allpursuing challenges.The Indian government has alsotaken several initiatives towardsstreamlining the way biosimilars/SBPwill be regulated in our country therebyshowcasing India as a key player in thebiosimilar segment.Some of these include dissemination ofapplicable guidance documents; creatingadditional levels of checks (prescreeningchecklist for filing, NDAC referral),drafting of the Biotechnology RegulatoryAuthority of India bill, creating publicawareness through several meetings withstakeholders and hosting clarificationson CDSCO site. These steps wouldensure more affordable biosimilar drugs““Generic drugs are the exact same chemically astheir brand name counterparts and they act thesame way in the body.being manufactured and made availableto patients both in domestic andexport markets.Conclusion:It’s an exciting time for biosimilars. Theneed of the hour is to conduct “SWOT”analysis and strengthen our competenceand confidence by understanding theregulatory guidelines and implementingthem as per current requirements.As such the regulatory guidelines willcontinue to evolve as we get moreexperienced and biosimilars continuehitting the market. We will also seedemand for biosimilar CMC developmentcontinue to grow as it plays a critical rolein demonstrating comparability to thereference product. As we are dealing withan inherently variable system, we need tolook at biosimilars development from anintegrated standpoint. Biotechnologicalmedicines shall become an importantpart of future healthcare landscape.With patent expiration of innovatorproducts, the biosimilars will increasinglybecome available. Awareness of thedeviations between biosimilars andinnovator products in terms of efficacy,safety and immunogenicity is essentialfor proper prescription and safetyof the patients.1. Quality Issues2. Efficacy Issues3. Safety Issues4. Pharmacovigilance5. Substitution6. Naming and Labeling7. Regulatory ApprovalFigure 3: Regulatory issues for the use of biosimilars