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15. Dr. Inger Mollerup - Novo Nordisk
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“Comparability of biotherapeutic products following manufacturing process improvement. Quality aspects and comparability issues” …

“Comparability of biotherapeutic products following manufacturing process improvement. Quality aspects and comparability issues”

Focuses on improvements in manufacturing processes of biotherapeutics

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  • The Bottom Line:
  • The data required by FDA to ensure that a product is safe and effective after a manufacturing change varies with the change. Significant manufacturing changes require significant supporting data.
  • Comparability following a process change is a different technical exercise to a comparison that an FOB manufacturer might make. Innovators who make process changes will not only compare the DP, they will also test and provide regulators with data from hundreds of other tests that have been conducted during the manufacturing process. Results from each step will be compared in order to understand the impact of the process change. An FOB manufacturer cannot perform these tests as they do not have access to the data – thus making their exercise of comparing the FOB to the innovator fundamentally different in the type and number of tests performed, to those undertaken by an innovator following a process change. Examples: The “light bulb” example would have been picked up in the in-process controls The California to Colorado change in site and consequent change in oxygen partial pressure would have been picked up in in-process controls and process validation Even though the FOB manufacturer can test against the drug product of the innovator, these tests are sometimes limited by the excipients. For example, components of the drug substance can “interfere” with the analytical tests. This means that it is not always possible to draw definitive conclusions from this comparison about similarity of the FOB and the innovator.
  • a lot of authorities elute to the standards made in EU how does it relate to IO
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  • 1. Comparability of biotheurapeuticproducts following manufacturingprocess improvementQuality aspects and comparability issuesInger MollerupCorporate Vice PresidentRegulatory AffairsNovo Nordisk A/S
  • 2. Manufacturing of biologics: each process isuniqueTransferPlasmidinto HostCellCell culture orfermentationPurify DrugSubstanceFormulateProduct forUseDownstreamProcessingClone Geneinto DNAVectorBiosimilarMaybeA differentformulationDifferentPurificationprotocolProbablydifferent DNAvectorSame AA -maybe samegeneticsequenceDifferentRecombinantcell systemDifferentIn-processcontrolsSlide no 213 Feb 2013
  • 3. Specifications are linked to the entire manufacturing process (ICHQ6B)Cell BankManuf.processDrugsubstanceDrugproductQ5B Genetic stab.Q5B Cell substrateQ5B Viral safety evaluationQ6B Specifications of biotech productQ5B Stability of biotech productTox studiesClinical studiesBiosimilarSlideno 313 Feb 2013
  • 4. Comparability exercise and Process changesChangefiltersupplierMoveequipmentdifferent partof facilityMovemanufacturingto new facilityNew cell lineNew ProcessNew FormulationScale-upManufacturingManufacturing Change•Low risk•Frequent•Supportedby:Analytical andProcess Data•Highest risk•Rare•Extensive Data:Analytical, Processand Human dataBiosimilarsNew:•DNA?•Cell line•Process Technology?•Fermentation process•Purification process•Analytics•Facilities•Formulation?•And - no historyStepwise Comparability exercise:Clinical ComparabilityNonclinical ComparabilityChemical ComparabilityCharacter of ChangeComplete Comparabilityexercise:Clinical ComparabilityNonclinical ComparabilityChemical Comparability
  • 5. Presentation title Slide no 5DateHow is a biosimilar designed?Target probably well defined”Design space”?
  • 6. The Comparability Concept for BiosimilarsAnalytical data + nonclinical and clinical dataInnovator Testing Following a ProcessChangeBiosimilarTestingPre-change Post-change New processIn process controls(15 – 50 tests)In process controls(15 – 50 tests)No comparison possibleProcess validation(5 – 15 tests)Process validation(5 – 15 tests)No comparison possibleStability profile(25 – 50 tests)Stability profile(25 – 50 tests)No comparison possibleDegradation profile(25 – 50 tests)Degradation profile(25 – 50 tests)No comparison possibleDrug substance QC(10 – 25 tests)Drug substance QC(10 – 25 tests)No comparison possibleDrug product QC(10 – 25 tests)Drug product QC(10 – 25 tests)Drug product QC(10 – 25 tests)Non-clinical testing(tox and others)Non-clinical testing(tox and others)Human studiesEfficacy, safety,immunogenicityHuman studiesEfficacy, safety,immunogenicityAdapted from: T. Lubiniecki (2005)ManufacturingProcess StepsCell expansionProductionRecoveryPurificationCharacterisationStabilityDrugSubstanceDrug ProductDrug ProductDrug Product
  • 7. Biosimilars, Overview of Scientific/Regulatory Guidelines and Experience, Inger Mollerup Novo Nordisk Slide no 7Oct 08 2009Innovator examples
  • 8. BiomassClear broth with secreted insulinprecursorPurified insulin precursorInsulin esterInsulin esterHuman Insulin (crude)Purified Human InsulinCell removalCapture processPurificationHydrolysisPurificationEnzymatic conversionNovo NordiskExpression system: S. CerevisiaeExpressed molecule:• Insulin precursor (3 AA bridge)No refolding neededDifferent•HCP’s•reagents•solvents•pH ranges•etc. etc. etc.DifferentExpressionSystemsEli LillyExpression system: E. ColiExpressed molecule:• Pro-Insulin (35 AA bridge)Unfolding and refoldingBiomassInclusion BodiesTrp-LE-Met-ProinsulinProinsulin (unfolded)Proinsulin-SSO3Proinsulin (refolded)Human Insulin (crude)Purified Human InsulinCell harvestingCell disruptionIB recoveryIB dissolutionCNBr cleavageOxidative sulfitolysisFolding, S-S bond formationEnzymatic conversionPurificationBiosimilarSlideno 813 Feb 2013
  • 9. HI derivatives originating from fermentationAsnCysTyrAsnGluLeuGlnTyrLeuSerIleCysSerThrCysCysGlnGluValIleGlyProLysThrTyrPhePheGlyGluArgGlyCysLeuValLeuAla TyrLeuGluValHisCysGlySerLeuHisValGlnAsnPheSSSS SSDesPhe(B1)-HIThr(A8)-O-mannosyl HIThrDesPhe(B1)-Val(B2)-HIB1A10A21B30B20B10A1ArgO-MannosylB0Arg-HIO-Glycosylation site
  • 10. ImpuritiesB29GlnAsnAsnCysTyrAsnGluLeuGlnTyrLeuSerIleCysSerThrCysCysGlnGluValIle GlyProLysThrTyrPhePheGlyGluArgGlyCysLeuValLeuAla TyrLeuGluValHisCysGlySerLeuHisValPheSSSSLysAlaAlaSSB1A21B20B10A1B29GlnAsnAsnCysTyrAsnGluLeuGlnTyrLeuSerIleCysSerThrCysCysGlnGluValIle GlyProLysThrTyrPhePheGlyGluArgGlyCysLeuValLeuAla TyrLeuGluValHisCysGlySerLeuHisValPheSSSSSSAlaAlaLysB1A21B20B10A1B22GlnAsnAsnCysTyrAsnGluLeuGlnTyrLeuSerIleCysSerThrCysCysGlnGluValIle GlyGluArgGlyCysLeuValLeuAla TyrLeuGluValHisCysGlySerLeuHisValPheSSSSSSB1A21B20B10A1B29GlnAsnAsnCysTyrAsnGluLeuGlnTyrLeuSerIleCysSerThrCysCysGlnGluValIle GlyProLysThrTyrPhePheGlyGluArgGlyCysLeuValLeuAla TyrLeuGluValHisCysGlySerLeuHisValPheSSSSSSB1A21B20B10A1B29GlnAsnAsnCysTyrAsnGluLeuGlnTyrLeuSerIleCysSerThrCysCysGlnGluValIle GlyProLysThrTyrPhePheGlyGluArgGlyCysLeuValLeuAla TyrLeuGluValHisCysGlySerLeuHisValPheSSSSSSLysAlaAlaB1A21B20B10A1IM1/IM3 IM5DOI S-comp.IM2/IM4
  • 11. BiosimilarPharmacopeia compliance is not a guaranteeTestSpecification Method of AnalysisIdentification A by Assay Complies Ph Eur, USPIdentification B by Peptide mapping Complies Ph Eur, USPBioidentity ≥15 USP U/mg USPHigh molecular weight proteins ≤1.0% Ph Eur, USPRelated proteins:Insulin human related substancesA21 desamido insulinhumanInsulin human related impurities≤2.0%≤2.0%Ph EurZinc(calculated on dried basis)≤1.0% Atomic absorptionPh EurLoss on drying ≤10.0% Ph Eur, USPSulphated ash(calculated on dried basis)≤2.5% Ph EurMicrobial control, total viable count ≤300 CFU/g Ph Eur, USPBacterial endotoxins ≤10 IU/mg Kinetic chromogenic methodPh Eur method D, USPAssay(calculated on dried basis)95.0 – 105.0%≥27.5 USP U/mgPh Eur, USPSlideno 1113 Feb 2013
  • 12. Biosimilars, Overview of Scientific/Regulatory Guidelines and Experience, Inger Mollerup Novo Nordisk Slide no 12Oct 08 2009An Entirely New Manufacturing ProcessNovo Nordisk Case Studies• Insulin Product• New production cell, DNA, cell bank• Optimised fermentation, recovery and purification processes• New facility• Quality:• Full CMC + comparability:Minute differences in impurity profile• Clinical• Pharmacokinetics/Dynamics• Immunogenicity• FDA• No safety threshold for new impurities• Not known when “low” is “low enough”Even for a small product as insulin, clinical safety studies arenecessary to demonstrate the absence of clinically meaningfuldifferences
  • 13. Biosimilars, Overview of Scientific/Regulatory Guidelines and Experience, Inger Mollerup Novo Nordisk Slide no 13Oct 08 2009Haemophilia Product (rFVIIa): InnovatorProcess Change Requiring New BLAChange in host cell line led to change in glycosylation patternHuman PK study revealed significant difference• New cell line (CHO) evaluated postapproval and compared with originalcell line (BHK)• Quality: Comparability data showeddifferences in glycosylation• N-acetyl-galactosamine (GalNAc)present in BHK-rFVIIa only (~20%)• Slightly lower content ofterminal sialic acid residueson BHK-rFVIIa comparedwith CHO-rFVIIa.• Clinical• Pharmacokinetic (BE) study• Further data required• Safety/Efficacy• Immunogenicity• FDA:• Requires new BLA and substantialclinical studiesComparative Human PK*Mean AUC for CHO 30%> than for BHK* Submitted for publication
  • 14. Biosimilars, Overview of Scientific/Regulatory Guidelines and Experience, Inger Mollerup Novo Nordisk Slide no 14Oct 08 2009Myozyme® (rhGAA) Example: Scale UpResulted in Different Product Characteristics• Orphan drug produced in CHO cells, both 160 litre and 2000 litrecell culture scale needed for supply• EMEA:• Concerns with regard to the potential levels of process impurities andpossible immunogenicity of CHO cell impurities for the 160L scale• Impurity profile of 2000L process improved compared to 160L process• Clinical experience from the 2000L process was taken into account• The 2000L product (only) was granted market authorisation• New facility recently approved• FDA:• FDA decided that batches manufactured in the two scales are different(incl. differences in glycosylation) and therefore constitute distinctproducts that must be licensed separately (separate BLA’s) andmarketed under different trade names• Genzyme submitted Lumizyme® for FDA approvalNot yet possible to link quality attributes to clinical S&E
  • 15. Biosimilars, Overview of Scientific/Regulatory Guidelines and Experience, Inger Mollerup Novo Nordisk Slide no 15Oct 08 2009Biosimilar Case Studies
  • 16. Product class-specific GuidelinesEU „Biosimilarity“ GuidelinesEMA GuidelinesBiosimilarGuideline on similar biological medicinal productGuidelines on similar biological medical products containingbiotechnology derived proteins as active substancesQuality Non-clinical/ClinicalRhInsulinSomatropin rG-CSF Epoetin Interferonα LMWH mAbs2013 reviewAnaloguesHM longacting 2013review2013finalise2013finalise + β2013reviewSlideno 1613 Feb 2013
  • 17. Bundesinstitut für Arzneimittelund MedizinproduktePrinciples of Biosimilar Approach „Similarity“ in terms of quality, safety and efficacy To a reference product licensed in the EU(Reference product: licensed based on full application,data protection expired) Same reference product for all aspects of thecomparability exercise
  • 18. Biosimilar Approvals In Europe to Date:Negative opinions and withdrawalsTrade Name Common NameInternationalNonproprietaryNameBiosimilarSponsor(s)ReferenceProductDecision Decision DateAlpheon®Interferon alfa-2a BioPartnersRoferon-A®Negative Opin. Jun 2006Insulin Rapid Marvel Soluble Insulin Marvel Humulin®Withdrawn Jan 2008Insulin Long Marvel Isophane Insulin Marvel Humulin®Withdrawn Jan 2008Insulin 30/70 MixMarvelBiphasic Insulin Marvel Humulin®Withdrawn Jan 2008Epostim® Epoietin RelianceGenemedixEprex®Withdrawn Apr 2011Insulin Solumarv Soluble Insulin Marvel Humulin®Withdrawn Dec 2012Insulin Isomarv Isophane Insulin Marvel Humulin®Withdrawn Dec 2012Insulin Combimarv Biphasic Insulin Marvel Humulin®Withdrawn Dec 2012EMA Public Assessment Report
  • 19. Marvel Insulins: Human Long, Rapid and Mix (2008)• Not possible to conclude that purity is comparable to referenceproduct• Clinical (PK/PD) data: Significant differences in bioavailability compared toreference products• Products were not biosimilar, file withdrawn from EMAPD data/LongPD studies demonstrated clinically meaningful differencesClinical safety and efficacy study confirmed differencePD data/Mix* Source: European Public Assessment ReportBiosimilarSlideno 1913 Feb 2013
  • 20. Marvel Insulins: Human Long, Rapid and Mix (2012)• Company reason:• Sufficient time to repeat andsubmit bioequivalence T1D PK/PDdata on each clamp study• Comply with the planned newinsulin guideline• Validated CRO• CHMP• Manufacturing concerns• Similarity was questionedBiosimilarSlideno 2013 Feb 2013
  • 21. Biosimilar Approvals In Europe to DateTrade Name Common NameInternationalNonproprietaryNameBiosimilarSponsor(s)ReferenceProductDecision Decision DateOmnitrope®somatropin Sandoz Genotropin®Approved Apr 2006Valtropin®somatropin BioPartners Humatrope®Approved Apr 2006“Sandoz EPO”Abseamed®Epoetin alfa HexalBinocrit®epoetin alfaMediceHexalSandozEprex®Approved Aug 2007“Hospira EPO”Silapo®Retacrit®epoetin zetaStadaHospiraEprex®Approved Dec 2007“Teva G-CSF”Tevagrastim®Ratiograstim®Filgrastimratiopharm (MAwithdrawn July2011)Biograstim®FilgrastimTevaRatiopharmCTArzneimittleNeupogen®Approved Sep 2008“Sandoz G-CSF”Filgrastim HexalZarzio®FilgrastimHexalSandozNeupogen® Approved Feb 2009Nivestim® Filgrastim Hospira UK Neupogen®Approved Jun 2010EMA Public Assessment Report
  • 22. Biosimilars, Overview of Scientific/Regulatory Guidelines and Experience,Inger Mollerup Novo NordiskSlideno 22Oct 08 2009EU: Early version of Omnitrope® (somatropin)Reference product: Genotropin (Pfizer)• Early version of the product: 57% of patients developedantibodies against Omnitrope• Problem was residual host-cell protein• Re-developed purification process• Conducted a second phase 3 study• Antibody levels reduced (comparable)• Approved by EMEA, FDA, TGA – and recently by Health Canadaand PMDA in JapanLink between quality parameter (HCP) and clinical safety(immunogenicity) found in clinical studies* Source: European Public Assessment Report
  • 23. Biosimilars, Overview of Scientific/Regulatory Guidelines and Experience,Inger Mollerup Novo NordiskSlideno 23Oct 08 2009EU: Alpheon (alpha interferon)Reference product: Roferon (Roche)• Differences in impurity profile were observed• Key Clinical Data• PK (3 studies):supra-bioavilability(early study); comparable; inconclusive• PD (2 studies): PD equivalence/no PD equivalence• Safety&Efficacy:• Clinically and statistically significant difference invirological relapse rate found: more patients onAlpheon had relapse• Different rate of adverse events and laboratory-related events judged as clinically relevantClinical studies evaluating efficacy and safety demonstratedclinically meaningful differences leading to Rejection by EMEA* Source: European Public Assessment Report
  • 24. Biosimilars, Overview of Scientific/Regulatory Guidelines and Experience, Inger Mollerup Novo Nordisk Slide no 24Oct 08 2009Other products - not approved under biosimilarframework
  • 25. Biosimilars, Overview of Scientific/Regulatory Guidelines and Experience, Inger Mollerup Novo Nordisk Slide no 25Oct 08 2009”Ex-EU” Somatropin: New Thioether VariantIdentified• Thioether variant found in somehGH products (up to ~30%)• Hormotrop®, Yelit®, Cryotropin®• Thioether variant not identified in• Saizen®• International standards:NIBSC 98/574 (r), NIBSC 80/505 (p),EP r-hGH CRS• Thioether variant:• Not detected by compendial and otherexisting chromatographic methods –new methods required• Generated by high pH at elevated temparature (40 deg C)• Significantly reduced biopotency in rat model• Analytical methods must be ”tailor made”* Lispi, M. et al, J. Pharm. Sciences, DOI 10 1002/jps 21774, 2009New impurity identified with reduced biopotencyChange in Clinical efficacy & safety cannot be excluded
  • 26. Biosimilars, Overview of Scientific/Regulatory Guidelines and Experience, Inger Mollerup Novo Nordisk Slide no 26Oct 08 2009Conclusion: Quality Aspects and Comparability• Products must have highly similar molecular structuralfeatures• Amino acid sequence must be the same• Glycosylation patterns must be highly similar• Same host cell type system• Impurity profiles must be highly similar• Analytical methods extremely important• Only way to exclude clinically meaningful differences inefficacy, safety and immunogenic potential – is from clinicaldata• Multiple examples illustrate close link between chemical andclinical comparability• Can’t be predicted from structure• Full comparability exercise needed – quality, nonclinicaland clinical – as outlined in EMEA guidance documents