Opportunities and Challenges in Biosimilar Development: Focus N..
Opportunities and Challenges in Biosimilar Development: Focus N..
Opportunities and Challenges in Biosimilar Development: Focus N..
BIOSIMILARS
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Pankaj S. Chaudhari, Rajalaxmi Nath, and Sanjeev K. Gupta
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biosimilar biotherapeutic Regulatory Framework
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product is similar (but not of Biosimilars
identical) in terms of quality, Table 4 presents biosimilar regulatory
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safety, and efficacy to an pathways for Europe and the United
already licensed reference product. States. The European Union (EU)
Unlike generic small molecules, it is pioneered development of regulatory
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difficult to standardize such inherently requirements for biosimilars in 2005.
complex products based on complicated The EMA also was the first regulatory
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manufacturing processes. Table 1 agency to authorize biosimilars for
describes the main differences between STOCK.ADOBE.COM
market. Europe’s extensive experience
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biosimilar and generic drug molecules. gained with licensed biosimilars has led
The global biosimilar market is have on patients in terms of safety and to robust regulatory processing by the
growing rapidly as patents on efficacy. EMA, with a recent guideline revision
blockbuster biologic drugs expire
M
Developing and manufacturing adopted by the Committee for Human
(Table 2) and other healthcare sectors biosimilars is challenging, so well- Medicinal Products (CHMP) on
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focus on reduction of costs. Biologics established biopharmaceutical October 2014. In 2015, the first US
are among the highest-cost treatments companies are investing in these biosimilar — Zarxio (filgrastim) from
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on the global market today, which important medicines. As Table 3 shows, Sandoz — encouraged development of
implies the need for low-cost Europe is leading the way. The United biosimilars for that country as well.
P
alternatives. In emerging markets, States approved its fourth biosimilar in The US Food and Drug
biosimilars already offer more September 2016, compared with 15 Administration (FDA) released its final
affordable prices, which are not only products — marketed under 26 distinct biosimilar guideline on 28 April 2015.
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attractive, but indispensable to brands — already approved by the Biosimilar Nomenclature: The
economies where expensive treatments European Medicines Agency (2, 3). The complex nature of biological
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are not financially feasible (1). market will continue to grow as best- molecules requires specific
Interchangeability of biosimilars could selling biologics come off patent in nomenclature guidelines. Naming
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have a big impact on drug budgets coming years (4). Hundreds of biosimilars has further increased this
around the world. However, concerns companies worldwide are developing complexity, and to date, several
remain about the effect that could biosimilars to target diverse markets. different and inconsistent conventions
T
characterization similar but not identical to reference generic product is identical to International Nonproprietary Name
products that of the reference product
(INN) system currently in place.
E
Manufacturing Very complex; produced in living cells, Relatively simple, uses organic
process with several stages of purification and medicinal chemistry reactions
The FDA defined how biologicals
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Manufacturing
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Table 4: Regulatory framework in Europe and the United States — differences between European Medicines Agency (EMA) and Food and Drug
Administration (FDA) pathways; areas of overlap are tinted.
Criteria EMA FDA
First approved biosimilar Omnitrope (somatropin), 2006 Zarxio (filgrastim-sndz), 2015
Biosimilar regulatory paradigm Demonstration that a potential biosimilar is highly similar to its reference product in safety, purity, and
potency/efficacy with no clinically meaningful differences
In vivo comparative toxicology Not required routinely, relies more on Routinely required, although the agency can waive this
studies in vitro evaluation of structure–function
relationships
Multistep comparison of a Analytical and functional studies; in vivo nonclinical analyses; clinical pharmacokinetic/pharmacodynamic
biosimilar to its reference assessments; head-to-head clinical trials in the most sensitive population(s) — safety, efficacy, and
product immunogenicity studies
Biosimilar review process Nontherapeutically aligned structure in centralized Therapeutically aligned structure with multiple levels of
CHMP reviews supervision and oversight
Legal pathway A separate branch of the generic pathway (Directive Biologics Price Competition and Innovation Act (BPCI
2001/83/EC, Article 10.4) Act) of 2009
Meetings between Centralized advice procedure by the EU CHMP FDA meeting structure defined by the Biosimilar User
developers/sponsors and Scientific Advice Working Party provides mostly Fee Act (BsUFA for biosimilar applications)
regulatory agencies written advice; meetings called when regulators
disagree with a sponsor’s proposed plan
Advice procedures with individual EU country health Biosimilar product development (BPD) meetings enable
authorities, usually involving meetings Biologic License Applications under 351(k) pathway
Interagency meetings EMA and FDA cluster meetings (closed, regulators-only meetings); EMA/FDA parallel advice (for companies)
products. That also is a question pharmacokinetic (PK) and/or consistently delivers products that meet
addressed by regulatory agencies when pharmacodynamic (PD) bridging quality attribute requirements. The
they evaluate biosimilars for approval. studies for all three products as well. level of control needed for each
Reference Standard Selection: The Extensive Comparability Data: individual quality attribute is
EMA has clear guidelines on use of Biological systems are inherently determined based on the criticality level
reference standards for similar biological variable, and expression systems can of that attribute and the capability of a
medicinal products (9). To facilitate the substantially affect the structure and process to deliver product consistently
global development of biosimilars and function of proteins they produce. Thus, that meets quality expectations.
prevent unnecessary repetition of biological products are extensively An integrated control strategy
clinical trials, it may be possible for an characterized for variability, even among includes procedural and raw-material
applicant to compare its biosimilar in different lots of the same product. controls, in-process control (IPC)
certain clinical studies and in vivo Stringent EMA and FDA regulations tests, process monitoring and product
nonclinical animal studies with a require comprehensive structural and data monitoring, release specification
reference product that is not authorized functional analytic comparative data to testing, stability testing, process
in the European Economic Area demonstrate comparability before validation, characterization testing,
(EEA), but that comparator should be initiating preclinical testing and clinical control of process validation, and
authorized by a regulatory authority PK/PD studies (10). comparability testing. Figure 3
with similar scientific and regulatory Biomolecular analyses fall under illustrates development of a control
standards (e.g., signatories to the three categories: physicochemical, strategy and its importance to product
International Council on immunological, and biological assays. lifecycle management
Harmonisation of Technical Table 5 summarizes those used in Establishment of specifications is a
Requirements for the Registration of comparability studies of biosimilar and major area of uncertainty for a biosimilar
Pharmaceuticals for Human Use, ICH). reference products. Demonstrating a integrated control strategy. Regulatory
According to the EMA biosimilar high level of analytical similarity expectations for commercial
guidelines (Figure 2), if an applicant between those drugs is the first step. specifications are not completely clear,
performs parallel development for All structural elements and however. EU guidance mentions that
Europe and the United States, then modifications of a protein should be selection of tests to be included in
inclusion of US reference standards is evaluated with full capability of specifications (or control strategy) is
necessary. Scientifically, the type of detecting differences. Based on product specific for both drug substance
bridging data needed always will observed characteristics of the reference and drug product, and thus should be
include data from analytical studies product, a quality target product profile defined as described in ICH Q6B (11).
(e.g., structural and functional data) (QTPP) is defined for a biosimilar. US guidance, however, offers no specific
that compare all three products (the Control Strategy: The term “control reference to expectations for development
proposed biosimilar, the EU reference strategy” refers to a combination of of a biosimilar control strategy.
product, and the US comparator). input, procedural, and testing controls Manufacturing Changes and
They may include data from clinical that ensure that a bioprocess Challenges: Some biosimilar
Reference product
characterization Continued
CPD P&PC PPQ process verification
Biosimilar product
and process
understanding
QBD Finalize
commercial
PQR control strategy Lifecycle
QTPP/PQ (routine testing). Management
assessment Evaluate risk of
commercial process
Raw- before process
material validation, refine Reevaluate to
assessment as appropriate. maintain and, if needed,
Identify CQA and improve control.
needs for process
control strategy.
CPD = commercial process development; QTPP = quality target product profile; P&PC = process/product characterization;
PPQ = process performance qualification; PQR = product quality risk assessment; QBD= quality by design
Table 5: Physicochemical and biological characterization methods for comparability studies of biosimilars (8)
Higher-order structure Disulfide structure, free thiol analysis, secondary and LC-ESI-MS peptide mapping, Elman assay, CD,
tertiary structure FTIR, antibody conformational array, X-ray
crystallography
Purity, charge heterogeneity, Thermal stability, monomer content, charged isoforms DSC, SEC-HPLC,SEC-MALS, SV-AUC,CE-SDS, IEF,
amino acid modification IEC-HPLC
Glycosylation Deamidation/oxidation/C-terminal variants, N-glycan LC-MS peptide mapping, LC-MS, CE-SDS, HPLC,
analysis, glycosylation, oligosaccharide profile, sialic acid HPAEC-PAD
analysis, monosaccharide content (fructose, GlcNAc,
galactose and mannose)
Potency Antigen and C1q binding, FcRn binding, antigen ELISA, SPR, cell-based neutralization assay, cell-
neutralization, apoptosis, CDC based apoptosis assay, cell-based CDC assay
FTIR: Fourier-transform infrared spectroscopy RP-HPLC = reversed-phase high-performance liquid chromatography; LC-ESI-MS = liquid chromatography with
electrospray ionization mass spectrometry; CD = circular dichroism; DSC = differential scanning calorimetry; SEC = size-exclusion chromatography; MALS =
multiangle light scattering; SV-AUC = analytical ultracentrifugation; CE-SDS = capillary electrophoresis with sodium-dodecyl sulfate; IEF = isoelectric focusing;
LC-MS = liquid chromatography with mass spectrometry; HPAEC-PAD = high-performance anion-exchange chromatography with pulsed amperometric detection;
ELISA = enzyme-linked immunosorbent assay; SPR = surface plasmon resonance; CDC = complement-dependent cytotoxicity
Coxinélis
Q11/Q11_Step_4.pdf. •
Guidelines/Quality/Q6B/Step4/Q6B_ Major Hurdle. Business Insider 30 April 2015; Web_Site/ICH_Products/Guidelines/Quality/
Guideline.pdf. www.businessinsider.com/biosimilars-
12 Islam MS, Alam MU, Amin M. A bioequivalence-and-interchangeability-2015-4.
Global Perspective of the Prospects and 20 Draft Guidance for Industry:
Challenges of an Awaiting Revolution of Considerations in Demonstrating Interchangeability Pankaj S. Chaudhari is regulatory affairs
Biosimilars. Biojournal Sci. Technol. 2, 2015: 7–16. with a Reference Product. US Food and Drug and quality assurance (RA/QA) manager
13 Biosimilarity and Comparibility After Administration: Rockville, MD, January 2017; ([email protected]), Rajalaxmi
Manufacturing Changes: Can a Biologic Become a www.gpo.gov/fdsys/pkg/FR-2017-01-18/ Nath is RA/QA research associate, and
Biosimilar of Itself? European pdf/2017-01042.pdf. corresponding author Sanjeev K. Gupta is
Biopharmaceutical Enterprises: Brussels, 21 Moorkens E, et al. Overcoming Barriers general manager of the advanced biotech
Belgium, 22 February 2016. to the Market Access of Biosimilars in the laboratory at Ipca Laboratories, Ltd. in
14 Hurley P, Borley J, Congiatu C. Challenges European Union: The Case Study of Biosimilar Mumbai, India; +91-22-6210-5820; sanjeev.
in Global Biosimilar Development: A Regulatory Monoclonal Antibodies. Front. Pharmacol. 7, [email protected]; www.ipca.com.
Perspective. Contract Pharma June 2015. 2016: 193; doi:10.3389/fphar.2016.00193.
15 Macdonald JC, et al. Regulatory 22 Rader RA. Biosimilars Pipeline
Considerations in Oncologic Biosimilar Drug Analysis: Many Products, More Competition To share this in PDF or professionally printed
Development. mAbs 7(4) 2015: 653–661; doi:10. Coming. BioProcess Online 26 July 2016. format, contact Rhonda Brown: rhondab@
1080/19420862.2015.1040973. 23 Biosimilar Market Is Projected to be fosterprinting. com, 1-866-879-9144 x194.
16 First Biosimilar with Extrapolation: Worth USD 32 Billion Worldwide by 2025
Interchangeability Is Next. FDAMap 18 According to “Global Biosimilars Market, 2015–
February 2016; www.fdamap.com/first- 2025.” GlobeNewswire: El Segundo, CA, 12
biosimilar-with-extrapolation- November 2015.
interchangeability-is-next.html.
Jennifer Cochran, Ph.D. Paul Carter, Ph.D. Catherine Coombes Keiichiro Suzuki
Stanford University Genetech, Inc. HGF Limited, UK Salk Institute