15. Dr. Inger Mollerup - Novo Nordisk
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“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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15. Dr. Inger Mollerup - Novo Nordisk
- 1. Comparability of biotheurapeutic products following manufacturing process improvement Quality aspects and comparability issues Inger Mollerup Corporate Vice President Regulatory Affairs Novo Nordisk A/S
- 2. Manufacturing of biologics: each process is unique Transfer Plasmid into Host Cell Cell culture or fermentation Purify Drug Substance Formulate Product for Use Downstream Processing Clone Gene into DNA Vector Biosimilar Maybe A different formulation Different Purification protocol Probably different DNA vector Same AA - maybe same genetic sequence Different Recombinant cell system Different In-process controls Slide no 213 Feb 2013
- 3. Specifications are linked to the entire manufacturing process (ICH Q6B) Cell Bank Manuf. process Drug substance Drug product Q5B Genetic stab. Q5B Cell substrate Q5B Viral safety evaluation Q6B Specifications of biotech product Q5B Stability of biotech product Tox studies Clinical studies Biosimilar Slide no 3 13 Feb 2013
- 4. Comparability exercise and Process changes Change filter supplier Move equipment different part of facility Move manufacturing to new facility New cell line New Process New Formulation Scale-up Manufacturing Manufacturing Change •Low risk •Frequent •Supported by: Analytical and Process Data •Highest risk •Rare •Extensive Data: Analytical, Process and Human data Biosimilars New: •DNA? •Cell line •Process Technology? •Fermentation process •Purification process •Analytics •Facilities •Formulation? •And - no history Stepwise Comparability exercise: Clinical Comparability Nonclinical Comparability Chemical Comparability Character of Change Complete Comparability exercise: Clinical Comparability Nonclinical Comparability Chemical Comparability
- 5. Presentation title Slide no 5Date How is a biosimilar designed? Target probably well defined ”Design space”?
- 6. The Comparability Concept for Biosimilars Analytical data + nonclinical and clinical data Innovator Testing Following a Process Change Biosimilar Testing Pre-change Post-change New process In process controls (15 – 50 tests) In process controls (15 – 50 tests) No comparison possible Process validation (5 – 15 tests) Process validation (5 – 15 tests) No comparison possible Stability profile (25 – 50 tests) Stability profile (25 – 50 tests) No comparison possible Degradation profile (25 – 50 tests) Degradation profile (25 – 50 tests) No comparison possible Drug substance QC (10 – 25 tests) Drug substance QC (10 – 25 tests) No comparison possible Drug 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 studies Efficacy, safety, immunogenicity Human studies Efficacy, safety, immunogenicity Adapted from: T. Lubiniecki (2005) Manufacturing Process Steps Cell expansion Production Recovery Purification Characterisatio n Stability Drug Substance Drug Product Drug Product Drug Product
- 7. Biosimilars, Overview of Scientific/Regulatory Guidelines and Experience, Inger Mollerup Novo Nordisk Slide no 7Oct 08 2009 Innovator examples
- 8. Biomass Clear broth with secreted insulin precursor Purified insulin precursor Insulin ester Insulin ester Human Insulin (crude) Purified Human Insulin Cell removal Capture process Purification Hydrolysis Purification Enzymatic conversion Novo Nordisk Expression system: S. Cerevisiae Expressed molecule: • Insulin precursor (3 AA bridge) No refolding needed Different •HCP’s •reagents •solvents •pH ranges •etc. etc. etc. Different Expression Systems Eli Lilly Expression system: E. Coli Expressed molecule: • Pro-Insulin (35 AA bridge) Unfolding and refolding Biomass Inclusion Bodies Trp-LE'-Met-Proinsulin Proinsulin (unfolded) Proinsulin-SSO3 Proinsulin (refolded) Human Insulin (crude) Purified Human Insulin Cell harvesting Cell disruption IB recovery IB dissolution CNBr cleavage Oxidative sulfitolysis Folding, S-S bond formation Enzymatic conversion Purification Biosimilar Slide no 8 13 Feb 2013
- 9. HI derivatives originating from fermentation Asn Cys Tyr Asn Glu Leu GlnTyrLeuSer Ile Cys Ser Thr Cys Cys Gln Glu Val Ile Gly Pro Lys Thr Tyr Phe Phe Gly Glu Arg Gly Cys Leu Val LeuAla Tyr Leu Glu Val His Cys Gly Ser Leu His Val Gln Asn Phe S S S S S S DesPhe(B1)-HI Thr(A8)-O-mannosyl HI Thr DesPhe(B1)- Val(B2)-HI B1 A10 A21 B30 B20 B10 A1 Arg O-Mannosyl B0Arg-HI O-Glycosylation site
- 10. Impurities B29 Gln Asn Asn Cys Tyr Asn GluLeuGlnTyrLeu Ser Ile Cys Ser Thr Cys Cys Gln Glu Val Ile Gly Pro Lys Thr Tyr Phe Phe Gly Glu Arg Gly Cys Leu ValLeuAla Tyr Leu GluVal His Cys Gly Ser Leu His Val Phe S S S S Lys Ala Ala S S B1 A21 B20 B10 A1 B29 Gln Asn Asn Cys Tyr Asn GluLeuGlnTyrLeu Ser Ile Cys Ser Thr Cys Cys Gln Glu Val Ile Gly Pro Lys Thr Tyr Phe Phe Gly Glu Arg Gly Cys Leu ValLeuAla Tyr Leu GluVal His Cys Gly Ser Leu His Val Phe S S S S S S AlaAlaLys B1 A21 B20 B10 A1 B22 Gln Asn Asn Cys Tyr Asn GluLeuGlnTyrLeu Ser Ile Cys Ser Thr Cys Cys Gln Glu Val Ile Gly Glu Arg Gly Cys Leu ValLeuAla Tyr Leu GluVal His Cys Gly Ser Leu His Val Phe S S S S S S B1 A21 B20 B10 A1 B29 Gln Asn Asn Cys Tyr Asn GluLeuGlnTyrLeu Ser Ile Cys Ser Thr Cys Cys Gln Glu Val Ile Gly Pro Lys Thr Tyr Phe Phe Gly Glu Arg Gly Cys Leu ValLeuAla Tyr Leu GluVal His Cys Gly Ser Leu His Val Phe S S S S S S B1 A21 B20 B10 A1 B29 Gln Asn Asn Cys Tyr Asn GluLeuGlnTyrLeu Ser Ile Cys Ser Thr Cys Cys Gln Glu Val Ile Gly Pro Lys Thr Tyr Phe Phe Gly Glu Arg Gly Cys Leu ValLeuAla Tyr Leu GluVal His Cys Gly Ser Leu His Val Phe S S S S S S Lys Ala Ala B1 A21 B20 B10 A1 IM1/IM3 IM5 DOI S-comp. IM2/IM4
- 11. Biosimilar Pharmacopeia compliance is not a guarantee Test Specification Method of Analysis Identification A by Assay Complies Ph Eur, USP Identification B by Peptide mapping Complies Ph Eur, USP Bioidentity ≥15 USP U/mg USP High molecular weight proteins ≤1.0% Ph Eur, USP Related proteins: Insulin human related substances A21 desamido insulin human Insulin human related impurities ≤2.0% ≤2.0% Ph Eur Zinc (calculated on dried basis) ≤1.0% Atomic absorption Ph Eur Loss on drying ≤10.0% Ph Eur, USP Sulphated ash (calculated on dried basis) ≤2.5% Ph Eur Microbial control, total viable count ≤300 CFU/g Ph Eur, USP Bacterial endotoxins ≤10 IU/mg Kinetic chromogenic method Ph Eur method D, USP Assay (calculated on dried basis) 95.0 – 105.0% ≥27.5 USP U/mg Ph Eur, USP Slide no 11 13 Feb 2013
- 12. Biosimilars, Overview of Scientific/Regulatory Guidelines and Experience, Inger Mollerup Novo Nordisk Slide no 12Oct 08 2009 An Entirely New Manufacturing Process Novo 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 are necessary to demonstrate the absence of clinically meaningful differences
- 13. Biosimilars, Overview of Scientific/Regulatory Guidelines and Experience, Inger Mollerup Novo Nordisk Slide no 13Oct 08 2009 Haemophilia Product (rFVIIa): Innovator Process Change Requiring New BLA Change in host cell line led to change in glycosylation pattern Human PK study revealed significant difference • New cell line (CHO) evaluated post approval and compared with original cell line (BHK) • Quality: Comparability data showed differences in glycosylation • N-acetyl-galactosamine (GalNAc) present in BHK-rFVIIa only (~20%) • Slightly lower content of terminal sialic acid residues on BHK-rFVIIa compared with CHO-rFVIIa. • Clinical • Pharmacokinetic (BE) study • Further data required • Safety/Efficacy • Immunogenicity • FDA: • Requires new BLA and substantial clinical studies Comparative 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 2009 Myozyme® (rhGAA) Example: Scale Up Resulted in Different Product Characteristics • Orphan drug produced in CHO cells, both 160 litre and 2000 litre cell culture scale needed for supply • EMEA: • Concerns with regard to the potential levels of process impurities and possible 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 distinct products that must be licensed separately (separate BLA’s) and marketed under different trade names • Genzyme submitted Lumizyme® for FDA approval Not 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 2009 Biosimilar Case Studies
- 16. Product class-specific Guidelines EU „Biosimilarity“ Guidelines EMA Guidelines Biosimilar Guideline on similar biological medicinal product Guidelines on similar biological medical products containing biotechnology derived proteins as active substances Quality Non-clinical/Clinical Rh Insulin Somatropin rG-CSF Epoetin Interferonα LMWH mAbs 2013 review Analogues HM long acting 2013 review 2013 finalise 2013 finalise + β 2013 review Slide no 16 13 Feb 2013
- 17. Bundesinstitut für Arzneimittel und Medizinprodukte Principles 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 the comparability exercise
- 18. Biosimilar Approvals In Europe to Date: Negative opinions and withdrawals Trade Name Common Name International Nonproprietary Name Biosimilar Sponsor(s) Reference Product Decision Decision Date Alpheon® Interferon alfa-2a BioPartner s Roferon-A® Negative Opin. Jun 2006 Insulin Rapid Marvel Soluble Insulin Marvel Humulin® Withdrawn Jan 2008 Insulin Long Marvel Isophane Insulin Marvel Humulin® Withdrawn Jan 2008 Insulin 30/70 Mix Marvel Biphasic Insulin Marvel Humulin® Withdrawn Jan 2008 Epostim® Epoietin Reliance Genemedi x Eprex® Withdrawn Apr 2011 Insulin Solumarv Soluble Insulin Marvel Humulin® Withdrawn Dec 2012 Insulin Isomarv Isophane Insulin Marvel Humulin® Withdrawn Dec 2012 Insulin Combimarv Biphasic Insulin Marvel Humulin® Withdrawn Dec 2012 EMA Public Assessment Report
- 19. Marvel Insulins: Human Long, Rapid and Mix (2008) • Not possible to conclude that purity is comparable to reference product • Clinical (PK/PD) data: Significant differences in bioavailability compared to reference products • Products were not biosimilar, file withdrawn from EMA PD data/Long PD studies demonstrated clinically meaningful differences Clinical safety and efficacy study confirmed difference PD data/Mix * Source: European Public Assessment Report Biosimilar Slide no 19 13 Feb 2013
- 20. Marvel Insulins: Human Long, Rapid and Mix (2012) • Company reason: • Sufficient time to repeat and submit bioequivalence T1D PK/PD data on each clamp study • Comply with the planned new insulin guideline • Validated CRO • CHMP • Manufacturing concerns • Similarity was questioned Biosimilar Slide no 20 13 Feb 2013
- 21. Biosimilar Approvals In Europe to Date Trade Name Common Name International Nonproprietary Name Biosimilar Sponsor(s) Reference Product Decision Decision Date Omnitrope® somatropin Sandoz Genotropin® Approved Apr 2006 Valtropin® somatropin BioPartners Humatrope® Approved Apr 2006 “Sandoz EPO” Abseamed® Epoetin alfa Hexal Binocrit® epoetin alfa Medice Hexal Sandoz Eprex® Approved Aug 2007 “Hospira EPO” Silapo® Retacrit® epoetin zeta Stada Hospira Eprex® Approved Dec 2007 “Teva G-CSF” Tevagrastim® Ratiograstim® Filgrastim ratiopharm (MA withdrawn July 2011) Biograstim® Filgrastim Teva Ratiopharm CT Arzneimittle Neupogen® Approved Sep 2008 “Sandoz G-CSF” Filgrastim Hexal Zarzio® Filgrastim Hexal Sandoz Neupogen® Approved Feb 2009 Nivestim® Filgrastim Hospira UK Neupogen® Approved Jun 2010 EMA Public Assessment Report
- 22. Biosimilars, Overview of Scientific/Regulatory Guidelines and Experience, Inger Mollerup Novo Nordisk Slide no 22 Oct 08 2009 EU: Early version of Omnitrope® (somatropin) Reference product: Genotropin (Pfizer) • Early version of the product: 57% of patients developed antibodies 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 Canada and PMDA in Japan Link 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 Nordisk Slide no 23 Oct 08 2009 EU: 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 in virological relapse rate found: more patients on Alpheon had relapse • Different rate of adverse events and laboratory- related events judged as clinically relevant Clinical studies evaluating efficacy and safety demonstrated clinically 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 2009 Other products - not approved under biosimilar framework
- 25. Biosimilars, Overview of Scientific/Regulatory Guidelines and Experience, Inger Mollerup Novo Nordisk Slide no 25Oct 08 2009 ”Ex-EU” Somatropin: New Thioether Variant Identified • Thioether variant found in some hGH 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 other existing 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, 2009 New impurity identified with reduced biopotency Change in Clinical efficacy & safety cannot be excluded
- 26. Biosimilars, Overview of Scientific/Regulatory Guidelines and Experience, Inger Mollerup Novo Nordisk Slide no 26Oct 08 2009 Conclusion: Quality Aspects and Comparability • Products must have highly similar molecular structural features • 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 in efficacy, safety and immunogenic potential – is from clinical data • Multiple examples illustrate close link between chemical and clinical comparability • Can’t be predicted from structure • Full comparability exercise needed – quality, nonclinical and clinical – as outlined in EMEA guidance documents
Notes de l'éditeur
- 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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