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
Istituto di Farmacologia
Università Cattolica del S. Cuore
Il valore dell’informazione sui farmaci biosimilari, tra innovazione e sostenibilità
Roma, 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.
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»
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.
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.
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 processMANUFACTURERS 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 processL’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.You can also read
