Come nasce un farmaco biosimilare. Sviluppo, produzione, controlli - Pierluigi Navarra - Evento 18 Settembre 2018

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Come nasce un farmaco biosimilare. Sviluppo, produzione, controlli - Pierluigi Navarra - Evento 18 Settembre 2018
Come nasce un farmaco biosimilare.
  Sviluppo, produzione, controlli

                          Pierluigi Navarra

                                       Istituto di Farmacologia
                                       Università Cattolica del S. Cuore

Il valore dell’informazione sui farmaci biosimilari, tra innovazione e sostenibilità
                            Roma, 18 Settembre 2018
Come nasce un farmaco biosimilare. Sviluppo, produzione, controlli - Pierluigi Navarra - Evento 18 Settembre 2018
COSA SONO I BIOSIMILARI?

                                                   EMA                                                                                                                  FDA

                                                                                                                                               • A biological product that is highly similar to
      • A biological medicinal product that contains a
                                                                                                                                                    the reference product notwithstanding minor
           version of the active substance of an already
                                                                                                                                                    differences in clinically inactive components
           authorised original biological medicinal product
                                                                                                                                                    and
           and
                                                                                                                                               • There are no clinically meaningful
      • Demonstrates similarity to the reference
                                                                                                                                                    differences from the reference product in
           medicinal product in terms of quality
                                                                                                                                                    terms
           characteristics, biological activity, safety, and
                                                                                                                                                    of the safety, purity, and potency2
           efficacy based on a comprehensive
           comparability exercise1
•   FDA = Food and drug administration; EMA = European medicines agency.
    1. EMA. Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues, 2014;
    2. FDA. Scientific considerations in demonstrating biosimilarity to a reference product. Guidance for industry, 2015.
Come nasce un farmaco biosimilare. Sviluppo, produzione, controlli - Pierluigi Navarra - Evento 18 Settembre 2018
I FARMACI BIOLOGICI SONO ESTREMAMENTE PIÙ COMPLESSI E VARIABILI DELLE
MOLECOLE DI SINTESI CHIMICA
           Chemically
           Synthesized
                                                         Biologic Drugs
           Drugs
                               Bacteria or Yeast                             Mammalian Expression System2,3
                             Expression Systems1                                        mAbs
                                                                                        • Complex structure, consist
                           Insulin                                                        of multiple domains6
                           • FDA regulated as a                                         • Post-translational
                             small molecule and                                           modifications6
                                                                              1 ,7
                                                                           i ty
                             not as a biologic4
                                                                      p lex
                           • Small, with 51 amino                   om
                                                              n   gC
                             acids5
                                                        reasi
                           • Well characterized5     Inc
                           • Nonglycosylated5

               Aspirin8     Insulin9                 GH110               hFSH11                   mAbs6
              ~ 0.18 kDa   ~ 5.8 kDa                ~ 22 kDa            ~ 48 kDa                ~ 150 kDa

         generici                           Biosimilari                                      «Biosimilari 2.0»
Come nasce un farmaco biosimilare. Sviluppo, produzione, controlli - Pierluigi Navarra - Evento 18 Settembre 2018
IL PROCESSO DI CULTURA CELLULARE È CARATTERIZZATO DA PARAMETRI CHE
      POSSONO AVERE UN IMPATTO ALTISSIMO SULLA MOLECOLA FINALE
                                                                                                                                                                             Bioreactor
                                                                                                                                                                                                                   Motor: RPM2,4

                                                                                                                                                                                                                     Gases4:
                                                                                                                                   Feed2          Alkali3                                                           N2, O2, CO2

                                                                                                                                     Probe outputs:
                                                                                                                                   temperature, pH,                                                                Cell and growth
                                                                                                                                   dissolved oxygen2                                                                    media2

•   N2 = nitrogen; O2 = oxygen; CO2 = carbon dioxide; RPM = revolutions per minute.
•   Amgen Inc. An Introduction to Biotechnology. www.amgen.com/pdfs/misc/An_Introduction_Biotechnology.pdf. Accessed February 10, 2012. 2. Martin I, et al. Trends Biotech. 2004;22:80-86. 3. Langheinrich C, et
    al. Biotechnol Bioeng. 1999;66:171-179. 4. Rodrigues C, et al. Biotechnology Advances. 2011;29:815-829.
Come nasce un farmaco biosimilare. Sviluppo, produzione, controlli - Pierluigi Navarra - Evento 18 Settembre 2018
LO SVILUPPO E LA PRODUZIONE DI UN BIOSIMILARE DIFFERISCE DA QUELLA DI UNA
          MOLECOLA DI SINTESI, E DI UN BIOLOGICO INNOVATIVO

                                                                                 Generics                           Biologic Biosimilars                           Biologic new drug
                                                                                       Low2                                                                               High2
                                                 SCIENTIFIC
                                                 DIFFICULTY
                                                                                                                                              Biosimilarity1
                                   Development

                                                                                   Short3                                                                               Long (10+
                                                                                 (3–4 years)                                                                             years)4
                                                 TIME
                                                                                                                                           ~ 8 Years
                                                                               Low (< $5M)                                                                            High (> $800M)
                                                                             Bioequivalence3                                                                       Clinical development4
                                                 COST
                                                                                                                                       ~ $200 M3
                                                 MANUFACTURIN
                                   Ops

                                                                               Short, simple5                                                                        Long, complex5
                                                 G PROCESS
                                                                                                                                                Complex1

                         CONOSCENZE SCIENTIFICHE AVANZATE ED ECCELLENZA NELLA PRODUZIONE SONO INDISPENSABILI
                                    PER SVILUPPARE UN BIOSIMILARE DI UN ANTICORPO MONOCLONALE
•   Ops = operations.
•   1. EMA. Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues (revision 1), 2014;
    2. Camacho LH, et al. Cancer Med 2014;3:889–99; 3. Federal Trade Commission. Emerging health care issues: follow-on biologic drug competition, 2009;
    4. Ventola CL. P T. 2013;38:270–87; 5. Roger SD. Nephrology (Carlton) 2006;11:341–46.
Come nasce un farmaco biosimilare. Sviluppo, produzione, controlli - Pierluigi Navarra - Evento 18 Settembre 2018
OGNI VOLTA CHE IL PRODUTTORE APPORTA DELLE MODIFICHE AD UN PROCESSO
      PRODUTTIVO DI FARMACI BIOLOGICI APPROVATI, È NECESSARIO UN ESERCIZIO DI
      COMPARABILITÀ 1
                                                   Nature of Process Change2,3                                                          Risk and Data Requirements2

                                         Commonly                                                                                    Low
                                        Implemented                         Change filter supplier                                   Risk
                                                                                                                                                      • Analytical data
                                                                                                                                                      • Process studies
                                                                             Replace equipment

                                                                                                                                 Moderate             • Analytical data
                                                                        Change cell culture media                                  Risk               • Process studies
                                                                                                                                                      • Stability data

                                                                             Change formulation
                                                                                                                                                      • Process studies
                                            Less                                                                                                      • Stability data
                                         Commonly                                                                                    High
                                                                        Change manufacturing site                                    Risk             • Clinical data
                                        Implemented

•   1. ICH Harmonised Tripartite Guideline, Comparability of biotechnological/biological products subject to changes in their manufacturing process
    Q5E, 2004;
    2. Lee JF, et al. Curr Med Res Opin 2012;28:1053–58; 3. Ramanan S, et al. BioDrugs 2014;28:363–72.
SVILUPPARE UN BIOSIMILARE RICHIEDE LA GENERAZIONE DI UN NUMERO
        MAGGIORE DI DATI RISPETTO ALLA DIMOSTRAZIONE DELLA COMPARABILITÀ DOPO
        UN CAMBIAMENTO PRODUTTIVO
    Per sviluppare un
                                                                                          Product    Process     Analytical   Nonclinical   Clinical
    biosimilare:                                                                          history   evaluation    studies      studies      studies

    • Mancano i dati storici sul                                 Modified process

        processo produttivo, se non
                                                                    Abbreviated
                                                                   comparability
                                                                (same manufacturer)
                                                                                           ü          ü            ü
        quelli presenti in letteratura

    • Bisogna ri-sviluppare le                                      New process
        conoscenze sul farmaco
                                                                   Comprehensive
                                                                    comparability
                                                                (same manufacturer)
                                                                                           ü          ü            ü             ü           ü
        originatore, tramite campioni
        commerciali

    • Si riparte da una nuova linea

        cellulare, sviluppando il
                                                                 Biosimilar process
                                                               (different manufacturer)    ?           ?           ü             ü           ü
                                                                                           Knowledge gap
        processo produttivo dall’inizio

•   Adapted from Declerck P, et al. Pharm Res 2016;33:261–8.
CHI PRODUCE BIOSIMILARI HA UNA CONOSCENZA LIMITATA DEL FARMACO DI
           ORIGINE
                                                                                                                                                                      Analytical
                                                              Known1                                                  Unknown2                                     Characterisation3,4
                                                                                                          § Cell line
                                                                                                          § Growth media
                                                                                                          § Method of cell
                                                                                                            expansion
                                                                                                          § Bioreactor conditions
                                                                                                          § Protein recovery
                                                                   DNA                                      conditions                                              Compare structure
                                                                                                          § Purification conditions                                 and function to the
                                                              sequence                                                                                              reference product
                                                                                                          § Formulation methods
                                                                                                          § Reagents
                                                                                                          § Reference standards

•   1. Roger SD. Nephrology (Carlton) 2006;11:341–6; 2. Mellstedt H, et al. Ann Oncol 2008:411–9;
    3. FDA. Scientific considerations in demonstrating biosimilarity to a reference product. Guidance for industry, 2015;
    4. EMA. Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues (revision 1), 2014.
I BIOSIMILARI VENGONO SVILUPPATI TRAMITE REVERSE ENGINEERING DEL
           BIOLOGICO ORIGINATORE

                                              Reference                                                                                                                   Biosimilar
                                              Product                                        REVERSE ENGINEERING1,2                                                       Candidate

                                              Characterize                        Identify                            Develop                              Characterise   Evaluate
                                              reference                           CQAs of                             unique cell                          biosimilar     similarity and
                                              product                             reference                           line and                             candidate      match CQAs
                                                                                  product                             manufacturing                                       to reference
                                                                                                                      process                                             product

•   CQAs = critical quality attributes.
    1. Kozlowski S. Oral presentation at Biotechnology Technology Summit, 2014;
    2. FDA. Quality considerations in demonstrating biosimilarity of a therapeutic protein product to a reference product. Guidance for industry, 2015;
    3. ICH Harmonised Tripartite Guideline, Comparability of biotechnological/biological products subject to changes in their manufacturing process Q5E, 2004;
    4. EMA. Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues (revision 1), 2014;
    5. EMA. Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues, 2014.
LA VALUTAZIONE DELLA SIMILARITÀ ANALITICA È IL FONDAMENTO DELLO SVILUPPO DI
BIOSIMILARI

                         Amino acid sequence and                          Target binding and
                         post-translational                                immunochemical
                         modifications, eg. glycans                                properties
                                                         Primary
                                                         structure

                                     Higher order                          Biological
                                      structure                             function     Quantitative levels of
                     Secondary,                        Product-related                   product variants and
                     tertiary, and          Uno sviluppatore di
                                                       substances and
                                                                                                their identities
                     quaternary         biosimilari può arrivare a
                                                          impurities
                     structure          testare piu di 100 attributi
                                                     Stability                             Degradation profiles
                                       General della molecola6                               denoting stability
                                                                Particles
                                      properties
                                                                             and
                                         and
                                                                          aggregates
                                      excipients
                                                          Process-
                                                           related              Subvisible and submicron
           Properties of the finished drug
                                                         impurities
           product including strength and                                        particles and aggregates
           formulation                                                                     of various sizes

                                             Impurities from host cells
                                             and downstream process
MANUFACTURERS ESTABLISH ACCEPTABLE RANGES
       OF VARIATION THROUGH EXTENSIVE CHARACTERIZATION AND MONITOR FOR
       ADHERENCE TO THESE SPECIFICATIONS

         Acceptable range of variation is established by the                                                                                                                Normal Variability in Final Product for mAb
       manufacturer on the basis of data from multiple batches
                                                                                                                                                                                    115%

                                                                                                                                                                                    110%

                                                                                                                                                                Product Attribute
                                                                                                                                                                                    105%

       During the development process, relationships between                                                                                                                        100%
      inputs and product attributes are studied to further inform
                                                                                                                                                                                    95%
                    normal range specifications
                                                                                                                                                                                    90%

                                                                                                                                                                                    85%

                                                                                                                                                                                             Production Lots
      During routine manufacturing process, input parameters
     and product quality attributes are monitored for adherence                                                                                            Reproduced from Ramanan S, et al. BioDrugs. 2014;28:363-372.
                                                                                                                                                           With permission from Springer International Publishing AG.
                   to normal variability standards

•   USL = upper specification limit; UCL = upper control limit; LCL = lower control limit; LSL = lower specification limit.

•   Ramanan S, et al. BioDrugs 2014;28:363–72;
    EMA. Guideline on similar biological medicinal products containing monoclonal antibodies – non-clinical and clinical issues, 2012;
    EMA. Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues (revision 1), 2014.
Small Variations in Structure Are Acceptable Provided Biologic Function
is Maintained
                                                                                                                                          Predefined margins are determined based
                            Example of heterogeneity                                                                                      44     on the reference product2,3
                        in glycosylation to the Fc region1
                                                                                                                                          39

                                                                                                           Glycosylation (%)*
                                                                                                                                          34
                                   Reference                                                                                                                                                                               Outside
                                                                                                                                                                                                                           predefined
                                    product                                                                                               29                                                                               quality range

                                                                                                                                          24
                                                                                                                                                                                                 Predefined
                                                                                                                                                                                                quality range
                                                                                                                                          19
                                                                                                                                          14
                                                                                                                                                                     Reference                               Biosimilar
                                                                                                                                                                      Product

                                                                                                                                                             140

                                                                                                                                Relative CDC Activity (%)*
                                  Biosimilar                                                                                                                 130
                                                                                                                                                             120
                                                                                                                                                             110
                                                                                                                                                             100
                                                                                                                                                                                                     Predefined
                                                                                                                                                              90                                    quality range

                                                                                                                                                              80
                                                                                                                                                              70
                                        L-fucose         N-acetyl-D-glucosamine                                                                               60
                                                                                                                                                                            Reference                              Biosimilar
                                        D-mannose             D-galactose                                                                                                    Product
                                                                                                                                                              *Each data point represents test results from a unique lot
1. Chirino AJ, et al. Nat Biotechnol 2004;22:1383–91; 2. Quast I, et al. J Clin Invest 2015;125:4160–70;
3. Tsong. J Biopharm Stat [ePub ahead of print] 2015.
LA VALUTAZIONE DELLA SIMILARITÀ ANALITICA È IL FONDAMENTO DELLO SVILUPPO DI
BIOSIMILARI

                         Amino acid sequence and                          Target binding and
                         post-translational                                immunochemical
                         modifications, eg. glycans                                properties
                                                         Primary
                                                         structure

                                     Higher order                          Biological
                                      structure                             function     Quantitative levels of
                     Secondary,                        Product-related                   product variants and
                     tertiary, and          Uno sviluppatore di
                                                       substances and
                                                                                                their identities
                     quaternary         biosimilari può arrivare a
                                                          impurities
                     structure          testare piu di 100 attributi
                                                     Stability                             Degradation profiles
                                       General della molecola6                               denoting stability
                                                                Particles
                                      properties
                                                                             and
                                         and
                                                                          aggregates
                                      excipients
                                                          Process-
                                                           related              Subvisible and submicron
           Properties of the finished drug
                                                         impurities
           product including strength and                                        particles and aggregates
           formulation                                                                     of various sizes

                                             Impurities from host cells
                                             and downstream process
L’ENTE REGOLATORIO RICHIEDE UN APPROCCIO “STEPWISE” PER I
                BIOSIMILARI

                                                                         Clinical Studies                                                                • Each step should reduce residual
                                                                         (Safety, efficacy,                                                                uncertainties from the preceding step2–4
                                INCREASING CERTAINTY

                                                                         immunogenicity)
                                                                                                                                                         • The nature and complexity of the reference
                                                              Clinical Pharm.
                                                                                                                                                           product, as well as access to published
                                                                  (PK/PD)                                                                                  information about the reference product, impact
                                                                                                                                                           the extent of the studies to confirm
                                                                                                                                                           biosimilarity2–4
                                                           In Vivo Studies
                                                             (Nonclinical)                                                                               • The development program is designed to
                                                                                                                                                           demonstrate that the biosimilar is highly
                                                                                                                                                           similar to the reference product, and not to
                                                       In Vitro Studies                                                                                    independently establish its safety and
                                                          (Analytical
                                                       characterisation)                                                                                   effectiveness2–4

                                                                                               Biosimilar Development1-3
         •       Ogni step reduce il grado di incertezza residuo, ed è necessario prima di passare a
                 quello successivo.
         •       Qualora venissero evidenziate delle differenze, devono essere giustificate tenendo
                 contro del loro potenziale impatto su efficacia e sicurezza
1. Kozlowski S. Oral presentation at Biotechnology Technology Summit, 2014;
2. FDA. Scientific considerations in demonstrating biosimilarity of a therapeutic protein product to a reference product. Guidance for Industry, 2015;
3. EMA. Guideline on similar biological medicinal products, 2014;
4. EMA. Guideline on similar biological medicinal products containing monoclonal antibodies – non-clinical and clinical issues, 2014.
I REQUISITI REGOLATORI RICHIESTI PER I BIOSIMILARI SONO DIVERSI
RISPETTO AI FARMACI BIOLOGICI INNOVATIVI
                                                    Originator Development1
                                 Demonstrate safety and effectiveness with adequate and
                                  well-controlled substantial evidence for a new product

                                                                                                                     Clinical Studies
                                                                                                                     (safety, efficacy,
                                                                                                                     immunogenicity)

                                                                                                      Clinical Pharmacology
                                                                                                                                                                               L’intero processo
                                                                                                              (PK/PD)                                                          corrisponde all
                                                                                                                                                                               “esercizio di
                                                                                                     In Vivo Studies                                                           comparabilità”
                                                                                                       (nonclinical)

                                                                                                 In Vitro Studies
                                                                                                    (analytical
                                                                                                 characterisation)
                                                                                                                                                   Biosimilar Development1-3
                                                                                                                          Demonstrate safety, purity, and potency in one or more appropriate
                                                                                                                            conditions of use for which the reference product is licensed
PK/PD = pharmacokinetics/pharmacodynamics.
1. Kozlowski S. Oral presentation at Biotechnology Technology Summit, 2014;
2. FDA. Scientific considerations in demonstrating biosimilarity to a reference product. Guidance for Industry, 2015;
3. EMA. Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues, 2014.
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