24 BioProcess International 15(5) May 2017

Opportunities and Challenges in Biosimilar DevelopmentPankaj S. Chaudhari, Rajalaxmi Nath, and Sanjeev K. Gupta

FOCUS ON... BIOSIMILARS

A biosimilar biotherapeutic product is similar (but not identical) in terms of quality, safety, and efficacy to an

already licensed reference product. Unlike generic small molecules, it is difficult to standardize such inherently complex products based on complicated manufacturing processes. Table 1 describes the main differences between biosimilar and generic drug molecules.

The global biosimilar market is growing rapidly as patents on blockbuster biologic drugs expire (Table 2) and other healthcare sectors focus on reduction of costs. Biologics are among the highest-cost treatments on the global market today, which implies the need for low-cost alternatives. In emerging markets, biosimilars already offer more affordable prices, which are not only attractive, but indispensable to economies where expensive treatments are not financially feasible (1). Interchangeability of biosimilars could have a big impact on drug budgets around the world. However, concerns remain about the effect that could

have on patients in terms of safety and efficacy.

Developing and manufacturing biosimilars is challenging, so well-established biopharmaceutical companies are investing in these important medicines. As Table 3 shows, Europe is leading the way. The United States approved its fourth biosimilar in September 2016, compared with 15 products — marketed under 26 distinct brands — already approved by the European Medicines Agency (2, 3). The market will continue to grow as best-selling biologics come off patent in coming years (4). Hundreds of companies worldwide are developing biosimilars to target diverse markets.

RegulatoRy FRamewoRk oF BiosimilaRs

Table 4 presents biosimilar regulatory pathways for Europe and the United States. The European Union (EU) pioneered development of regulatory requirements for biosimilars in 2005. The EMA also was the first regulatory agency to authorize biosimilars for market. Europe’s extensive experience gained with licensed biosimilars has led to robust regulatory processing by the EMA, with a recent guideline revision adopted by the Committee for Human Medicinal Products (CHMP) on October 2014. In 2015, the first US biosimilar — Zarxio (filgrastim) from Sandoz — encouraged development of biosimilars for that country as well. The US Food and Drug Administration (FDA) released its final biosimilar guideline on 28 April 2015.

Biosimilar Nomenclature: The complex nature of biological molecules requires specific nomenclature guidelines. Naming biosimilars has further increased this complexity, and to date, several different and inconsistent conventions have been applied around the world (6). Often, biosimilar and reference products may share the same name. Together with naming inconsistencies, that has led to concern over the strength of the World Health Organization’s International Nonproprietary Name (INN) system currently in place.

The FDA defined how biologicals should be named in a January 2017 guidance (7), which states that each biosimilar must have a proper name made up of a core name hyphenated to a four-letter suffix representing the developer. For example, Adalimumab-

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Table 1: Major difference between biosimilars and generic drugs

Characteristics Biosimilars Generic Chemical DrugsChemical structure

Complex, heterogeneous, with differences in protein folding and glycosylation

Simple, well defined, and chemically identical to a reference product

Analytical characterization

Almost impossible to fully characterize; similar but not identical to reference products

Ensures that active drug in a generic product is identical to that of the reference product

Manufacturing process

Very complex; produced in living cells, with several stages of purification and production

Relatively simple, uses organic medicinal chemistry reactions

Impact of a process change

Small changes in manufacturing process can alter final protein structure and function

Likely to be negligible because the end products are identical

Development cost

$100–200 million/molecule $3–5 million/molecule

Immunogenicity Immunogenic Mostly nonimmunogenic

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atto (Amjevita) is a biosimilar of AbbVie’s Humira drug.

Those FDA-designated suffixes should prevent inadvertent substitution of products. The agency states that these products thus will be distinguishable so that only products that have been approved as interchangeable biologicals (biosimilars) for a particular indication will replace innovator treatments for that indication. This is intended to prevent accidental alternation between different biological products that share the same core name.

Biosimilars are receiving approval in Europe before receiving it in the United States. However, no naming convention has been established in Europe to date. There, biosimilars share the same INN with innovator products, which can create confusion among healthcare professionals.

BiosimilaR Development anD manuFactuRing

Therapeutic proteins derived through recombinant DNA technology (Figure

1) can vary in their primary amino acid sequence or through modifications made to their amino acid chains (e.g., glycosylation, PEGylation, or addition of other side chains to form a secondary structure) and in their higher-order structure (e.g., folding to form a tertiary structure, more complex interactions to form a quaternary structure). Proprietary biomanufacturing processes and environmental conditions used in development of innovator products usually are difficult for biosimilar manufacturers to replicate. So biosimilars are highly unlikely to be completely identical to comparator products.

First, the DNA sequence that encodes a desired biosimilar is identified, isolated, inserted into a vector, and incorporated into the genome of a suitable host cell (e.g., bacterium or mammalian cell). Bacterial host cells are inexpensive and easy to grow, and they generate high product yields. But they cannot produce large, complex proteins such as MAbs. By contrast, mammalian cells do so, but they are more sensitive and costly, and they generate relatively low product yields. A master cell bank with identical cells that produce a desired protein is established through cell screening and selection. That bank is used to culture additional cells

Table 3a: Biosimilars approved on the European market (5); * CHMP positive opinion

INN Names Brand Names Company Names ApprovalsFilgrastim Accofil, Biograstim,

Filgrastim Hexal, GrastofilNivestim, RatiograstimTevagrastim, Zarzio

Accord Healthcare, CT Arzneimittel, Hexal, Apotex, Hospira, Ratiopharm, Teva Generics, Sandoz

18 Sep 2014, 15 Sep 2008, 06 Feb 2009, 18 Oct 2013, 08 Jun 2010, 15 Sep 2008, 15 Sep 2008, 06 Feb 2009

Adalimumab Amgevita, Solymbic Amgen 26 Jan 2017*, 26 Jan 2017*

Etanercept Benepali Samsung Bioepis 14 Jan 2016Infliximab Remsima, Flixabi,

InflectraCelltrion, Samsung Bioepis, Hospira

10 Sep 2013, 26 May 2016, 10 Sep 2013

Rituximab Truxima Celltrion 15 Dec 2016*

Epoetin zeta Retacrit, Silapo Hospira, STADA R&D 18 Dec 2007, 18 Dec 2007

Epoetin alfa Binocrit, Abseamed, Epoetin alfa

Sandoz, Medice Arzneimittel, Hexal

28 Aug 2007, 28 Aug 2007, 28 Aug 2007

Follitropin alfa Ovaleap Teva Pharma 27 Sep 2013Somatropin Omnitrope Sandoz 12 April 2006Insulin Abasaglar, Lusduna Eli Lilly/Boehringer

Ingelheim, Merck (MSD)9 Sep 2014, 4 Jan 2017

Enoxaparin sodium Inhixa Techdow Europe 15 Sep 2016Teriparatide Movymia STADA Arzneimitte 10 Nov 2016*

Table 2: Patent status of some innovator biologics (3)

INN NameReference Product

Exclusivity Expiration

EU USAAdalimumab Humaria 2018 2016Etanercept Enbrel 2015 2028Infliximab Remicade 2015 2018Rituximab Mabthera 2013 2018Bevacizumab Avastin 2022 2019Trastuzumab Herceptin 2014 2019Pegfilgrastim Neulasta 2017 2015Ranibizumab Lucentis 2022 2020

Figure 1: Biosimilar production: source of variation between manufacturers (24)

Same gene sequence

Cloning of speci�cgene into DNA vector

RecombinantDNA Plasmid

Transfer intohost cell

Cellexpansion

Protein productionin bioreactor

Protein recoverythrough �ltration

and centrifugation

Cloning, Protein Expression, and Production

Proteinpuri�cation by

chromatography

Puri�edbulk

Proteincharacterization

and stability

Formulation

Di�erentexpression

Di�erentcell line

Di�erent bioreactorconditions

Di�erent operatingconditions

Di�erent binding andelution conditions

Di�erent�lter

supplier

Di�erent methods,reagents, and

reference standards

Di�erentsuppliers ofexcipients

Protein Puri�cation and Formulation

Di�erent vector

at increasing scale under strictly defined conditions that optimize protein production.

In downstream processing, undesired proteins and other impurities are removed from culture supernatant. Harvested protein is analyzed for uniformity in its three-dimensional structure and potency using a number of analytical methods, including physicochemical and biological tests. Finally, the purified drug substance is formulated with added excipients (e.g., antioxidants, osmotic agents, and buffers), filled into containers and external packaging, then stored and shipped under appropriate environmental conditions.

Biosimilar use of different expression systems from those producing reference drugs can change a protein’s posttranslational modifications (e.g., glycosylation profile), which in turn can affect product safety or effectiveness (8). Modification of any steps in biomanufacturing (e.g., use of a different vector to create host cells,

systems for cell screening and selection to establish the master cell bank, culture media, methods for production or purification, and excipients) can alter the effectiveness and safety of a product. Thus, biosimilar manufacturers must assess

the effects of such changes using appropriate analytical methods, functional assays, and animal and clinical studies to ensure that such changes do not adversely affect the identity, quality, purity, potency, safety, or effectiveness of their

Table 3b: Biosimilars approved on the US market (5)

INN Name Brand Name Company Name Approval DateAdalimumab Amjevita Amgen 23 Sept 2016Insulin glargine Basaglar Eli Lilly and Boehringer Ingelheim 16 Dec 2015Etanercept Erelzi Sandoz 30 Aug 2016Infliximab Inflectra Pfizer (Hospira) 5 Apr 2016Filgrastim Zarxio Sandoz 6 Mar 2015

Figure 2: Reference standard requirements for biosimilar development in major markets

EU approvalEU reference product

USAapproval

USreferenceproduct

CMC bridgingPK/PD bridgingPediatric studies

CMCIn vitro nonclinical

In vivo nonclinical(repeat-dose toxicity,

immunotoxicity)

Phase 1 PK/PD

E�cacy,immunogenicity

CMC = chemistry, manufacturing, and controls; PK = pharmacokinetics; PD = pharmacodynamics

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28 BioProcess International 15(5) May 2017

products. That also is a question addressed by regulatory agencies when they evaluate biosimilars for approval.

Reference Standard Selection: The EMA has clear guidelines on use of reference standards for similar biological medicinal products (9). To facilitate the global development of biosimilars and prevent unnecessary repetition of clinical trials, it may be possible for an applicant to compare its biosimilar in certain clinical studies and in vivo nonclinical animal studies with a reference product that is not authorized in the European Economic Area (EEA), but that comparator should be authorized by a regulatory authority with similar scientific and regulatory standards (e.g., signatories to the International Council on Harmonisation of Technical Requirements for the Registration of Pharmaceuticals for Human Use, ICH).

According to the EMA biosimilar guidelines (Figure 2), if an applicant performs parallel development for Europe and the United States, then inclusion of US reference standards is necessary. Scientifically, the type of bridging data needed always will include data from analytical studies (e.g., structural and functional data) that compare all three products (the proposed biosimilar, the EU reference product, and the US comparator). They may include data from clinical

pharmacokinetic (PK) and/or pharmacodynamic (PD) bridging studies for all three products as well.

Extensive Comparability Data: Biological systems are inherently variable, and expression systems can substantially affect the structure and function of proteins they produce. Thus, biological products are extensively characterized for variability, even among different lots of the same product. Stringent EMA and FDA regulations require comprehensive structural and functional analytic comparative data to demonstrate comparability before initiating preclinical testing and clinical PK/PD studies (10).

Biomolecular analyses fall under three categories: physicochemical, immunological, and biological assays. Table 5 summarizes those used in comparability studies of biosimilar and reference products. Demonstrating a high level of analytical similarity between those drugs is the first step. All structural elements and modifications of a protein should be evaluated with full capability of detecting differences. Based on observed characteristics of the reference product, a quality target product profile (QTPP) is defined for a biosimilar.

Control Strategy: The term “control strategy” refers to a combination of input, procedural, and testing controls that ensure that a bioprocess

consistently delivers products that meet quality attribute requirements. The level of control needed for each individual quality attribute is determined based on the criticality level of that attribute and the capability of a process to deliver product consistently that meets quality expectations.

An integrated control strategy includes procedural and raw-material controls, in-process control (IPC) tests, process monitoring and product data monitoring, release specification testing, stability testing, process validation, characterization testing, control of process validation, and comparability testing. Figure 3 illustrates development of a control strategy and its importance to product lifecycle management

Establishment of specifications is a major area of uncertainty for a biosimilar integrated control strategy. Regulatory expectations for commercial specifications are not completely clear, however. EU guidance mentions that selection of tests to be included in specifications (or control strategy) is product specific for both drug substance and drug product, and thus should be defined as described in ICH Q6B (11). US guidance, however, offers no specific reference to expectations for development of a biosimilar control strategy.

Manufacturing Changes and Challenges: Some biosimilar

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 FDAFirst approved biosimilar Omnitrope (somatropin), 2006 Zarxio (filgrastim-sndz), 2015Biosimilar 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 studies

Not required routinely, relies more on in vitro evaluation of structure–function relationships

Routinely required, although the agency can waive this

Multistep comparison of a biosimilar to its reference product

Analytical and functional studies; in vivo nonclinical analyses; clinical pharmacokinetic/pharmacodynamic assessments; head-to-head clinical trials in the most sensitive population(s) — safety, efficacy, and immunogenicity studies

Biosimilar review process Nontherapeutically aligned structure in centralized CHMP reviews

Therapeutically aligned structure with multiple levels of supervision and oversight

Legal pathway A separate branch of the generic pathway (Directive 2001/83/EC, Article 10.4)

Biologics Price Competition and Innovation Act (BPCI Act) of 2009

Meetings between developers/sponsors and regulatory agencies

Centralized advice procedure by the EU CHMP Scientific Advice Working Party provides mostly written advice; meetings called when regulators disagree with a sponsor’s proposed plan

FDA meeting structure defined by the Biosimilar User Fee Act (BsUFA for biosimilar applications)

Advice procedures with individual EU country health authorities, usually involving meetings

Biosimilar product development (BPD) meetings enable Biologic License Applications under 351(k) pathway

Interagency meetings EMA and FDA cluster meetings (closed, regulators-only meetings); EMA/FDA parallel advice (for companies)

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manufacturers may need to make changes or alter their own manufacturing processes — for enhancement of product quality and yield, adherence to upgraded regulatory policies, or increased efficiency and improved reliability of the biomanufacturing process (12). Modifications to any biological product — whether originator or biosimilar — that result from manufacturing changes are subject to tight regulatory controls and limits (13). Table 6 illustrates such

changes and associated regulatory requirements during different stages of manufacturing.

Clinical Development: Clinical trials for biosimilars must demonstrate safety and efficacy comparable to their comparators through sequential PK/PD, immunogenicity, and efficacy/safety trials. Stand-alone phase 3 studies or combined phase 1–3 designs without supporting PK data are unlikely to be accepted by regulatory reviewers. Subject to a risk-based

approach, clinical comparability requirements vary by case. Three-arm phase 1 clinical trials can demonstrate comparability for a biosimilar and two licensed versions of the same reference product on different markets (e.g., Europe and the United States). That allows developers to proceed with pivotal phase 3 trials using a single version of the reference product for biosimilar approval in each respective market (14). Extrapolation from one indication to another is allowed by both

Figure 3: Control strategy during biosimilar development

Preclinical Phase 1 Phase 3 Filing Launch/postlaunch

Reference productcharacterization

Biosimilar productand process

understanding

CPD P&PC PPQContinued

process veri�cation

QBD

PQRQTPP/PQassessment

Raw-material

assessment

LifecycleManagement

Finalizecommercial

control strategy(routine testing).

Identify CQA and needs for processcontrol strategy.

Evaluate risk ofcommercial process

before processvalidation, re�ne

as appropriate.Reevaluate to

maintain and, if needed, improve control.

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)

Characteristics Attributes Analytical MethodsPrimary structure Amino acid sequence RP-HPLC, LC-ESI-MS, peptide mapping

Higher-order structure Disulfide structure, free thiol analysis, secondary and tertiary structure

LC-ESI-MS peptide mapping, Elman assay, CD, FTIR, antibody conformational array, X-ray crystallography

Purity, charge heterogeneity, amino acid modification

Thermal stability, monomer content, charged isoforms DSC, SEC-HPLC,SEC-MALS, SV-AUC,CE-SDS, IEF, IEC-HPLC

Glycosylation Deamidation/oxidation/C-terminal variants, N-glycan analysis, glycosylation, oligosaccharide profile, sialic acid analysis, monosaccharide content (fructose, GlcNAc, galactose and mannose)

LC-MS peptide mapping, LC-MS, CE-SDS, HPLC, HPAEC-PAD

Potency Antigen and C1q binding, FcRn binding, antigen neutralization, apoptosis, CDC

ELISA, SPR, cell-based neutralization assay, cell-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

the EMA and FDA for biosimilars, although it must be supported by strong scientific justification (15).

inteRchangeaBility

As with generic drugs, interchangeability would allow biosimilars to be substituted by pharmacists without the intervention of a prescribing doctor. This is the next big hurdle in the path of biosimilars, clearing which would create a real challenge to the reference products’ markets (16). Such substitution is what allows generic medicines to gain market share rapidly (17). However, some prescribers may have safety concerns.

Immunogenicity studies present an additional consideration, particularly for interchangeable biosimilars, although they generally are not required for manufacturing changes. But designation of interchangeability would allow pharmacists to substitute such a biosimilar for its reference like they do with small-molecule generic drugs (18). The candidate on which

switching studies would be conducted must be the same as that approved without an interchangeability designation. There is no higher regulatory standard for biosimilars, and the data burden to obtain a designation of interchangeability is increased (7).

To be considered interchangeable in the United States, biosimilars must (among other things) “be expected to produce the same clinical result as the reference product in any given patient,” according to the Biologics Price Competition and Innovation Act of 2009. Developers also must document that a patient could switch back and forth between the original and biosimilar products without increased risk. According to the FDA’s rules, neither biosimilars nor interchangeable drugs can have clinically meaningful differences in safety when compared with the originator products (19).

Interchangeability and substitution of biosimilars are not within the scope of EU regulatory approval, so there is

no agreed-upon definition of what interchangeability actually means to Europe and no inclusion of such information in the European Public Assessment Report (EPAR) (15). Currently, the United States is the only country allowing for a formal such designation among biologic products. A recent FDA draft guideline requires that sponsors show that a proposed product “is biosimilar to the reference product” (20). When a product is first licensed as a biosimilar, that licensure may be referenced to support the statutory criterion for demonstrating interchangeability on the basis of a switching study or studies.

oppoRtunities anD RecommenDations

Based on a literature review, we offer in Table 7 some recommendations to overcome barriers to the market access for biosimilar MAbs (21). Once such blockbusters start to go off patent in Europe, biosimilars should become 20–30% cheaper than original MAb products. Market competition will

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32 BioProcess International 15(5) May 2017

play a pivotal role in favor of biosimilars. These speculations come from the fact that a 30–40% price reduction already has been seen for epoetin and filgrastim (granulocyte colony-stimulating factor). The sole purpose of biosimilar development is to lower the cost relative to original biologics and take their market share.

IMS Health forecasts that the global biologics market should reach $250 billion by 2020. Until then, some blockbuster MAbs will continue to dominate because of their patent protection. Once biosimilar MAbs start to invade their market, however, the scenario will change dramatically. Biosimilars and nonoriginal biologics are likely to take 4–10% market share by 2020, worth about $10–25 billion. That anticipation hinges on the number of biosimilars, especially those introduced to the US market. The United States represents the largest potential market for biologics because of its high per capita consumption of biologics overall.

By 2020, the 12 products that share 40% of the current global biologic market (worth $72 billion in sales) will face patent expiration. Such a goldmine will be too lucrative for biosimilars to be kept away, and the race has begun already. In September 2013, the EMA

approved the first two biosimilar versions of Remicade (infliximab). Now, those two biosimilars together incur more sales than all the other biosimilars on the market combined (12). With the great majority of products in development targeted for US, EU, and other major markets, the current pipeline includes ~800 biosimilars and ~500 biobetters (a total of ~1,300 follow-on products) in development pipeline for >100 currently marketed biopharmaceutical reference products (22). The IMS Health report provides an extensive study of the rapidly growing market. As the biotechnology industry strives to minimize costs, biosimilars are viewed as viable substitutes to highly expensive innovator biological medications (23).

Demand for biologics is increasing in many healthcare sectors, more so than for small molecules. But the biosimilar landscape is replete with landmines of complications associated with regulatory, manufacturing, bioanalytical, and marketing concerns. Outsourcing could lead to cost-effective development while minimizing some challenges. And all can be overcome with an in-depth knowledge of each region, early strategic planning, and effective communication with regulatory

agencies. Successful development and commercialization of biosimilars requires business strategies that integrate appropriate clinical design and regulatory compliance.

Although it requires a substantial investment in time and money, the development and introduction of biosimilars ultimately should provide cost savings compared with innovator products. The growth rate for biosimilar MAbs might be over 25% by 2020. The industry of biosimilars should bring benefits both for science and for healthcare.

ReFeRences1 Ginestro M, Moore J. How to Compete

and Win in a World with Biosimilars: Commercial Launch Strategies and Defensive Positioning for the US. KPMG: Chadds Ford, PA, 2015.

2 Acha V. Countering Points Made in Biosimilars. Pharmaceut. J. 30 Jan 2017; www.pharmaceutical-journal.com/opinion/correspondence/countering-points-made-in-biosimilars-piece/20202218.article.

3 Rader RA. Manufacturing Costs Will Be Critical to Biosimilars’ Success. Pharmaceut. Manufact. 8 November 2016.

4 Rémuzat C. Key Drivers for Market Penetration of Biosimilars in Europe. J. Market Access Health Pol. 5(1) 2017; doi:10.1080/20016689.2016.1272308.

5 Biosimilars Approved in Europe. GaBI J. 24 February 2017; www.gabionline.net/Biosimilars/General/Biosimilars-approved-in-Europe.

6 Jensen AR. US FDA Proposals for Naming of Biologicals and Labelling of Biosimilars. GaBI J. 5(3) 2016: 140–143.

7 CBER/CDER. Nonproprietary Naming of Biological Products: Guidance for Industry. US Food and Drug Administration: Rockville, MD, January 2017.

8 Tsuruta LR, Santos ML. Biosimilar Advancements: Moving on to the Future. Biotechnol. Progr. 31(5) 2015: 1139–1149; doi:10.1002/btpr.2066.

9 CHMP/437/04 Rev 1. Guideline on Similar Biological Medicinal Products. European Medicines Agency: London, UK, 23 October 2014.

Table 7: Recommendations for overcoming challenges to market access

Barrier RecommendationManufacturing process Invest initially in advanced production processes with the help of

single-use technology. Outsource technology.Regulatory process Gain experience with regulatory process and establish alignment

between stakeholders. Engage in early dialogues with regulators.Intellectual property rights

Limit patent litigations. Eliminate evergreening benefits. Build out further the unitary patent and unified patent litigation system.

Impossibility of substitution

Change attitude toward biosimilar switching/substitution, starting with physician and patient education.

Innovator’s reach Differentiate biosimilars with service offerings. Use appropriate comparators in cost-effectiveness analyses.

Table 6: Manufacturing changes and regulatory recommendations

Development Stage Expected Changes Regulatory RecommendationsEarly stage(preclinical)

Change in cell line, fermentation process, raw materials used during fermentation; order of purification steps, replacement and/or removal of purification steps

Comparability testing generally not as extensive as for an approved product

Late stage(clinical)

Change in cell line, fermentation process, raw materials used during fermentation; order of purification steps, replacement and/or removal of purification steps; formulation of drug product and manufacture of drug product; new drug substance and/or new drug product

Extensive comparability studies to confirm/support that the pre- and postchange products are not different in quality, safety, and efficacy; data as per ICH Q11 (25)

After market authorization (postapproval changes)

Change in cell line, fermentation process/scale-up, raw materials; order of purification steps, replacement and/or removal of purification steps; formulation of drug product and manufacture of drug product; new manufacturing site

At this stage, product is not expected to change; any changes need careful investigation and justification for safety and efficacy; follow variation guideline

10 Navaneethaselvan D, et al. The Opportunities and Challenges Involved in Registration of Similar Biotherapeutic Products in Emerging Countries. Int. J. Res. Pharmacy Sci. 3(3) 2013: 6.

11 ICH Q6B. Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products. US Fed. Reg. 18 August 1999: 44928; www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q6B/Step4/Q6B_Guideline.pdf.

12 Islam MS, Alam MU, Amin M. A Global Perspective of the Prospects and Challenges of an Awaiting Revolution of Biosimilars. Biojournal Sci. Technol. 2, 2015: 7–16.

13 Biosimilarity and Comparibility After Manufacturing Changes: Can a Biologic Become a Biosimilar of Itself? European Biopharmaceutical Enterprises: Brussels, Belgium, 22 February 2016.

14 Hurley P, Borley J, Congiatu C. Challenges in Global Biosimilar Development: A Regulatory Perspective. Contract Pharma June 2015.

15 Macdonald JC, et al. Regulatory Considerations in Oncologic Biosimilar Drug Development. mAbs 7(4) 2015: 653–661; doi:10.1080/19420862.2015.1040973.

16 First Biosimilar with Extrapolation: Interchangeability Is Next. FDAMap 18 February 2016; www.fdamap.com/first-biosimilar-with-extrapolation-interchangeability-is-next.html.

17 Schueller T. Chances and Hurdles for Biosimilars. CHEManager Int. 8 October 2015; www.chemanager-online.com/en/topics/pharma-biotech-processing/chances-and-hurdles-biosimilars.

18 McCamish M, et al. Toward Interchangeable Biologics. Clin. Pharmacol. Ther. 97(3) 2015: 215–217; doi:10.1002/cpt.39.

19 Friedman LF. An Innovation That Could Transform the Drug Industry Faces a Major Hurdle. Business Insider 30 April 2015; www.businessinsider.com/biosimilars-bioequivalence-and-interchangeability-2015-4.

20 Draft Guidance for Industry: Considerations in Demonstrating Interchangeability with a Reference Product. US Food and Drug Administration: Rockville, MD, January 2017; www.gpo.gov/fdsys/pkg/FR-2017-01-18/pdf/2017-01042.pdf.

21 Moorkens E, et al. Overcoming Barriers to the Market Access of Biosimilars in the European Union: The Case Study of Biosimilar Monoclonal Antibodies. Front. Pharmacol. 7, 2016: 193; doi:10.3389/fphar.2016.00193.

22 Rader RA. Biosimilars Pipeline Analysis: Many Products, More Competition Coming. BioProcess Online 26 July 2016.

23 Biosimilar Market Is Projected to be Worth USD 32 Billion Worldwide by 2025 According to “Global Biosimilars Market, 2015–2025.” GlobeNewswire: El Segundo, CA, 12 November 2015.

24 A Health-System Pharmacist’s Guide to Biosimilars: Regulatory, Scientific, and Practical Considerations. American Society of Health-System Pharmacists: Bethesda, MD, 2013; http://ashpadvantagemedia.com/downloads/biosimcentral_guidelines.pdf.

25 ICH Q11: Development and Manufacture of Drug Substances. Federal Register 20 November 2012, Vol. 77, No. 224, p. 69634-5; www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q11/Q11_Step_4.pdf. •

Pankaj S. Chaudhari is regulatory affairs and quality assurance (RA/QA) manager (pankaj.chaudhari@ipca.com), Rajalaxmi Nath is RA/QA research associate, and corresponding author Sanjeev K. Gupta is general manager of the advanced biotech laboratory at Ipca Laboratories, Ltd. in Mumbai, India; +91-22-6210-5820; sanjeev.gupta@ipca.com; www.ipca.com.

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