The Importance of Characterization in Biosimilars Development - Pharmaceutical Technology

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The Importance of Characterization in Biosimilars Development
Industry experts discuss the requirements and challenges involved in getting a biosimilar product from bench to launch.


Pharmaceutical Technology
Volume 37, Issue 9, pp. 32-35
Fotosearch/getty images

The global market for biosimilar drugs has been forecasted to be $2.445 billion in 2013 according to a report by the British market-research firm, Visiongain (1). The growth corresponds to a 20% increase from last year’s figures and accounts for approximately 2% of the overall biologics market. Although narrowly focused on only a small number of therapy areas at present, the biosimilars market is set to expand over the next decade and beyond as a result of two major factors: the impending patent expiries on blockbuster biologics and the financial crisis that is driving payers to push for wider adoption of biosimilars to manage the escalating costs of healthcare.

Although many companies are keen on getting a share in the biosimilars market given its promising outlook, bringing these complex molecules from bench to launch can be a challenge, not just during the development stage but also in terms of the manufacturing process involved. Pharmaceutical Technology conducted a roundtable to gain further insight on this topic. Participants included: Sheen-Chung Chow, PhD, professor of the Department of Biostatistics and Bioinformatics at Duke University School of Medicine; Christina Satterwhite, PhD, director of laboratory sciences, Charles River; Fiona Greer, PhD, global director, BioPharma Services Development, Bruno Speder, team leader of clinical trial regulatory affairs, Clinical Research, and Rabia Hidi, PhD, director of biomarkers & biopharmaceutical testing, Laboratory Services, all three at Life Sciences Services at SGS.

The complex nature of biosimilars
PharmTech: Why are biosimilars not approved in the same way as generics?

Sheen-Chung Chow, PhD, professor, Department of Biostatistics and Bioinformatics,  Duke University  School of Medicine

Chow (Duke University): The regulatory approval pathway is well established for generic drugs; however, it cannot be applied to biosimilars due to the fundamental differences between generic drugs and biosimilars. For example, generic drugs are small-molecule drug products that contain “identical” active ingredient(s) as the branded drug. Biosimilars, on the other hand, are made of living cells or living organisms that are sensitive to environmental factors such as light and temperature during the manufacturing process. Biosimilars usually have mixed and complicated structures that are difficult, if not impossible, to characterize. As a result, biosimilars are not generic drugs.

Greer (SGS): Biosimilar drugs cannot be regarded in the same way as generics. The exact structure of small-molecule synthetic drugs and their impurities can be well defined chemically, which enables generic manufacturers to avoid full, costly clinical studies if they are able to establish that their product is “bioequivalent” in pharmacokinetic studies to the branded or listed drug. However, unlike small-molecule drugs, biologically derived products are large, complex protein molecules, usually comprising of a mixture of closely related species that undergo post-translational modifications, which influence the anticipated protein structure. When produced in mammalian expression systems, these proteins can also be glycosylated (i.e., the carbohydrate is attached to the protein backbone), thereby, further increasing the amount of heterogeneity in the glycoforms produced.

In addition, the complexities of cellular expression and biomanufacturing make exact replication of the originator’s molecule nearly impossible; the process will certainly be different. Moreover, parameters such as the three-dimensional structure, the amount of acido-basic variants, or post-translational modifications (e.g., the glycosylation profile) can be significantly altered by changes, which may initially be considered to be “minor” in the manufacturing process, but can greatly affect the safety and efficacy profiles of these products. Biosimilars are, therefore, not simple generics. The fundamental difference with complex protein molecules is that they cannot be absolutely identical to the original. Instead, companies developing these “copies” must demonstrate that they are similar by performing a side-by-side comparison with reference samples of the originator.

Christina Satterwhite, PhD, director of laboratory sciences, Charles River

Satterwhite (Charles River): Biosimilars are not approved in the same way as generics because they are similar but not identical to the original biological products due to the manufacturing processes used to generate these types of molecules. A biosimilar is a biologically derived product that can have subtle structural differences with each manufacturing process, which may result in different properties.

The road to approval
PharmTech:
Could you briefly describe the legal and regulatory approval pathways for biosimilars in Europe and United States?

Speder (SGS): Both the European and US regulatory pathways depend on being able to demonstrate “biosimilarity” involving rigorous comparison against batches of originator product, initially at the physicochemical level, then in a step-wise manner in safety, potency, and clinical studies. Only an originator product that was licensed on the basis of a full registration dossier can serve as a reference product (i.e., centralised procedure in Europe and new drug application in the US). Both in Europe and the US, extensive consultation with the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA), respectively, is required.

Greer (SGS): The European Union established the first legal regulatory guidelines for “similar biological medicinal products” i.e., biosimilars (2–4). Subsequently, specific product annexes were published (5). Several of the original guidelines have been, or are in the process of being, revised. The first biosimilar molecule approved in Europe in April 2006 was Omnitrope, a version of somatropin. All guidelines, plus current revision concept papers and drafts, are available on the EMA website (5).

Meanwhile, in the US, the Biologics Price Competition and Innovation Act (BPCIA) provides a new pathway for biosimilars—the 351(k) route of the Public Health Service (PHS) Act. This pathway also requires comparison of a biosimilar molecule to a single reference product that has been approved under the normal 351(a) route with reference to prior findings on safety, purity, and potency. In contrast, one aspect of the legislation unique to the US is the provision for two levels of product—“biosimilar” and “interchangeable biosimilar.” An interchangeable biological product is one that may be substituted for the reference product without the intervention of the healthcare provider who prescribed the reference product. Therefore, more data are required for a product to be labeled as interchangeable rather than biosimilar.

In February 2012, FDA published three draft guidance documents to assist biosimilar developers: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product (6), Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product (7) and Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009 (8). Earlier this year, a fourth guidance, dealing with scientific meetings, was issued (9).

Satterwhite (Charles River): The EU has developed a science-based regulatory guidance framework from 2005 to the present to ensure high-quality biosimilar drugs. The biosimilars pathway in the US was created under the Patient Protection and Affordable Care Act in 2010 (10); however, US regulations are still pending. Three draft guidances (6–8) were released in February 2012 with a focus on the analytical characterization and totality of evidence approach to the program. A fourth draft guidance (9) was released in 2013 that emphasized formal meetings between the sponsor and regulators. Many pharmaceutical and biotechnology companies are moving forward using the International Conference on Harmonization (ICH) and FDA regulatory guidances currently governing biologic submissions and strategies that incorporate the EU biosimilar regulatory guidance. Although the draft guidance is available, there remains some confusion within the industry.

Bioequivalence testing
PharmTech: Can you explain the procedures for testing the bioequivalence of biosimilars and how it differs from bioequivalence testing for generic drugs?

Chow (Duke University): The current regulation for approval of generic-drug products is based on testing for average bioequivalence. For assessment of biosimilars, it is suggested that testing for biosimilarity should focus on variability rather than average bioavailability alone. Besides, it has been criticized that the one-size-fits-all criterion is not appropriate for assessment of biosimilars.

Satterwhite (Charles River): One of the major differences in the testing of biosimilars as opposed to generics is that the drug-development package must not only test structure but also function. A biosimilar program should commence with a strong analytical package that typically incorporates the testing of protein quantity and purity, amino-acid sequence, glycosylation, physicochemical properties, and aggregation analysis. Lot release and stability testing should also be incorporated. In addition, these properties need to be known for the originator drug and multiple lots of the originator drug should, therefore, be evaluated.
The type of functional tests evaluated should be based on the mechanism of action of the drug. For example, an anti-CD20 monoclonal antibody may include the following assessments: antibody-dependent cell-mediated cytotoxicity (ADCC) assay, complement‑dependent cytotoxicity (CDC) assay, flow-cytometry apoptosis assay, flow-cytometry binding assay, and Fc receptor assays.

Bruno Speder,team leader of clinical trial regulatory affairs, Clinical Research, SGS

Speder (SGS): Testing the bioequivalence of biosimilars differs from that of standard generics, both in the nonclinical testing as well as in the design of the clinical studies. The bioequivalence of generics is compared in a randomized, two-period, two-sequence, single-dose, crossover-design study. The treatment periods should be separated by a wash-out period sufficient to ensure that drug concentrations are below the lower limit of bioanalytical quantification in all subjects at the beginning of the second period. Normally, at least five elimination half-lives are necessary to achieve this. In most cases, no nonclinical studies need to be conducted on the generic product.

For biosimilars, most of which have long half-lives, a crossover study would be ineffective and unethical due to the fact that the wash-out period would be quite long. The patient is not allowed to take the drug during this wash-out period, and hence, will have no treatment for their condition. Therefore, parallel-group studies are required, but these studies do not provide an estimate of within-subject variation. For biosimilars, extensive head-to-head nonclinical testing with the originator product is required.

The importance of characterization studies
PharmTech:
Why is structural and functional characterization especially important for biosimilars?

Satterwhite (Charles River): The analytical packages that are required for a robust program should be conducted prior to any in-vivo testing. The structural in-vitro tests, along with the functional in-vitro tests, provide necessary information to assess the biosimilarity of the molecules. Similarity is difficult to establish as different manufacturing processes can result in differences in glycosylation sites as well as aggregates. It is important that analytical tests including structural and functional characterization provide data in which subtle differences are revealed and risk assessment is conducted prior to continuing to the next step in the development program.

Fiona Greer, PhD, global director, biopharma services development, SGS

Greer (SGS): The development pathway for a biosimilar is unlike that of a novel biotherapeutic. Undoubtedly, there is an increased requirement for analytics. This enhanced analytical effort, which may be rewarded in the reduced requirement for clinical trials, entails initial physical, chemical, and biological characterization of the biosimilar in comparison to the originator reference product. If found to be “similar” during this extensive characterization, subsequent nonclinical and clinical data are then required to demonstrate the same safety and efficacy profiles as the originator compound. However, the premise is that the amount of nonclinical and clinical data required will be much less than for a novel stand-alone application, and generally, a Phase II trial is not necessary. Extensive studies should, therefore, be conducted to provide comparative data for the biosimilar side-by-side with the originator. Strategies at this stage must include assessment of primary and higher-order structure as well as batch-to-batch variation for both the biosimilar and the reference product. In practice, analytical characterization will follow the requirements of the ICH guideline Q6B, including determination of amino-acid sequence, post-translational modifications, including disulphide bridges and glycosylation, and spectroscopic profiles.

One of the most important analytical techniques for biomolecule structural characterization is mass spectrometry (MS). Usually several different types of instruments are used in the detailed study of a glycoprotein so that the overall structure can be elucidated, including electrospray–mass spectrometry (ES–MS), online ES–MS where the MS is coupled to a high-performance liquid chromatrography (HPLC), matrix-assisted laser-desorption ionization–mass spectrometry (MALDI–MS), and for derivatized carbohydrates, gas chromatography–mass spectrometry (GC–MS). Apart from the ability to study non-protein modifications such as sulphation and phosphorylation, the other major strength of an MS approach is in the analysis of mixtures, which has obvious applications in the analysis of heterogeneous glycoforms.

The objective of the comparative study is to establish whether the biosimilar has the same primary protein sequence of amino acids as the reference product. This can be done by using classical protein sequencing (automated Edman degradation), peptide MS-mapping, MS/MS sequencing and amino-acid analysis.

For products that are glycosylated, characterization of the carbohydrate structure is essential too. Glycosylation is arguably the most important of the numerous post-translational modifications, but what is undeniable is that it presents a unique challenge for analytical methods. The population of sugar units attached to individual glycosylation sites on any protein will depend on the host cell type used, but it will be a mixture of different glycoforms, on the same polypeptide. Powerful mass spectrometry (MS)-based strategies can be used to analyze both free (i.e., underivatized) and derivatized samples to determine sites of glycosylation of both N- and O-linked structures, the identity of terminal nonreducing ends (potentially the most antigenic structures), and the types of oligosaccharide present. Chromatographic anion-exchange methods can also be used for glycan profiling (i.e., the relative distribution of carbohydrate structures).

In addition to MS, a host of other analytical techniques should be used to compare the structure of both the biosimilar and originator at primary and higher-order levels. Various chromatographic, spectroscopic, and electrophoretic methods can be used to interrogate and compare on the basis of size, charge, and shape. Co- and post-translational modifications, fragmentation, aggregation, deamidation, and oxidation should all be studied and compared. Techniques such as near and far UV circular dichroism provide information on the folding and secondary and tertiary structure of the protein and can be used in a comparative sense. Depending on the molecule, non-routine techniques such as protein nuclear magnetic resonance (NMR) and x-ray crystallography may also be utilized. In fact, a whole panel of methods should be employed, including orthogonal techniques to analyze particular quality attributes. The concept of “fingerprinting” the molecule has been raised in the FDA guidelines.

It is clear from the new EU guidelines that the primary protein structure (i.e., the amino-acid sequence) must be the same. The guidelines, however, anticipate that minor differences in post-translational forms or product-related impurities may exist and that these products should be investigated with regard to their potential impact on safety and efficacy so that it is the total package of data that will be taken into account on a case-by-case basis. FDA has adopted a similar approach, in that the analytical characterization should show that it is “highly similar to the reference product notwithstanding minor differences in clinically inactive components.”

Rabia Hidi, PhD, director of biomarkers & biopharmaceutical testing, Laboratory Services, SGS

Hidi (SGS): An initial step of the comparability exercise is the analysis of the primary structure of the molecule. Change in the primary structure of a biotherapeutic compound could affect the down-stream higher-order composition, which could have impacts on the clinical activity. Essentially the tridimensional structures (tertiary or quaternary) are very important as they could greatly impact the biological function. Finally, post-transcriptional modifications (e.g., phosphorylation, glycosylation, lipid attachment and/or intentional modifications, such as PEGylation), should be thoroughly characterized as these can affect all forms of higher-order structure and can impact efficacy as well as immunogenicity in the clinic.

Functional assays for testing biological activity can play an important role in filling the gaps in data from higher-order structural qualities. Bioassays should be developed for high precision and sensitivity to detect in-vitro functional differences between the biosimilar and the reference compound. These assays should express the relative potency in which the activity of the biosimilar is determined by comparison to the reference compound according to European Pharmacopoeia and US Pharmacopeia recommendations.

Ideally, bioassays should allow an assessment of all functional domains of a biosimilar candidate during comparison to the originator. An example of multifunctionality is the therapeutic monoclonal antibodies (mAbs). Conventional assays for testing the functions of Fab and Fc domains of therapeutic antibodies are widely available. These include in-vitro target binding (either on intact cells or using soluble target), ADCC, CDC, programmed cell death (PCD) and surface plasmon resonance (SPR) Fc receptor binding assays.

PharmTech: What are the safety issues that must be considered when developing a biosimilar product?

Hidi (SGS): Safety of biosimilars is a crucial consideration. An important difference between biopharmaceuticals and conventional drugs with regard to safety is the significant potential to induce an immune response, known as immunogenicity. The intrinsic structural and physicochemical heterogeneity of biopharmaceuticals and the complex manufacturing process have the potential to affect their safety and efficacy. The potential for immunogenicity of a biosimilar should always be investigated in comparison with the originator product. The amount of immunogenicity data required will depend on the reference product and/or the product class.

Assays for pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity testing for biosimilar comparability studies should be developed and validated following the published regulatory guidance documents, white papers as well as other publications on PK and immunogenicity immunoassay validation for biologics in general (11–26). Unfortunately, none of these publications address specific challenges associated to the applicability of these assays in the comparability exercise between the biosimilar and the originator. Some key bioanalytical challenges are summarized below.

The immunogenicity of a similar biological medicinal product must always be investigated and studied head to head with the reference product.  State-of-the-art platforms and methods are available for testing immunogenicity of biosimilar products and could be deployed with appropriate sensitivity and specificity. A stepwise approach should be used to test the immunogenicity for biosimilar compounds. Samples are analyzed initially using a screening assay with sufficient sensitivity to detect low titer and low affinity antidrug antibodies (ADAs). After that, ADA-positive samples are tested using a confirmatory assay, which is generally built on the same format as the screening assay with sufficient specificity. Finally, true positive samples are tested using an assay based on the aptitude of ADA to neutralize a biological activity using an in-vitro assay.

During the validation of immunogenicity assays, standard methods and international standards should be used whenever possible. Interference with the matrix and with circulating drug should be thoroughly evaluated to offer specific and selective assays. Long-term testing of the methods and batch-to-batch testing of reagent performance must be performed as long-term follow-up data for immunogenicity are required for pre-licensing of biosimilars.

To fulfill the requirement for comparability exercise, immunogenicity should be tested in samples from two arms of the comparability study, from subjects receiving the biosimilar drug and those receiving the originator. The challenge is whether to develop one assay to test ADAs for both compounds (i.e., using one set of labeled drug reagent to detect both biosimilar and originator ADAs) or to develop two assays (i.e., each set of labeled drug reagent is used to detect its respective ADA). Using one assay format is the most conservative approach for comparing the immunogenicity of the biosimilar to the originator because there is no between assay variability to take into account when interpreting immunogenicity data from the two arms of the comparability study (for the biosimilar and for the comparator).

The trend within the industry for developing PK assays for biosimilar programs is that one assay should be applied to quantify both biosimilar and originator analytes in the samples. Since the assay will be used to support the comparability studies between the biosimilar and the originator, it is preferable to keep the same assay conditions as much as possible (e.g., the same platform, the same set of reagents). Other key challenges associated with PK assays are:

  • Calibration curve: biosimilar, originator, or two curves?
  • Quality-control (QC) samples: should both sets of QCs from the biosimilar and the originator samples be used during the validation and the establishment of the assay criteria?
  • Equivalency: how to establish the criteria to demonstrate "equivalency"?

Assays for PD analysis are less challenging and only one assay format should be used to analyze samples from both treatment groups (biosimilar and the originator) from the comparability study. A fit for purpose validation should be applied following the recommendations and guidelines for validating ligand-binding assays.

The data from pre-authorization clinical studies are usually too limited to identify all the potential unwanted effects of a biosimilar. Close monitoring of the clinical safety is necessary in the post-marketing phase, especially since rare adverse events are unlikely to be encountered in the limited clinical-trial populations. As for “regular” biologics, a pharmacovigilance plan should be submitted with the marketing authorization application. Any specific safety monitoring imposed on the reference product (or product class) should be incorporated into the pharmacovigilance plan. Potential additional risks identified (e.g. increased immunogenicity that might result from a difference in the glycosylation profile) should be closely followed up. As with the other aspect of biosimilars, the safety profile should be extensively discussed with EMA and FDA.

Satterwhite (Charles River): Most biosimilar programs include PK and PD studies in animals and humans. Preclinical studies would most likely include in-vivo studies to assess the similarity of the PK/PD profiles in a head-to-head study, including dose groups for both the biosimilar and originator molecules.  This strategy can help to ensure biological similarity between the biosimilar and originator biotherapeutics prior to conducting clinical studies. Biological differences between the molecules established during the preclinical stage could save time and money that may be wasted in a large clinical study if tested much later in development. 

Assay support for these programs would include UV-spectrophotometry and size exclusion (SEC) high-performance liquid chromatography (HPLC) methods for the dose formulation concentration determination of the biosimilar and originator biotherapeutics, large molecule PK assays, immunogenicity, and any other assays required to assess the PD endpoint (i.e., the mechanism of action of the drug will dictate which assays would be required).

Validation of these assays is required and should commence early in the program to avoid validation being the rate limiting step.  Similarity of the biotherapeutics should be evaluated in each assay and in-vivo study. The data should be taken together to assess the overall similarity of the molecules.

Chow (Duke University): In terms of interchangeability, the BPCI Act in the US indicates that we should expect to see same results in any given patients. In practice, it is not possible to demonstrate same clinical results in any given patients. It is, however, possible to show same clinical results in any given patients "with certain statistical assurance."

References:

  • Visiongain, “Biosimilars and Follow-On Biologics: World Market 2013–2023,” www.visiongain.com/Report/1039/Biosimilars-And-Follow-On-Biologics-World-Market-2013-2023, accessed Aug. 5, 2013.
  • EMA, Guideline on Similar Biological Medicinal Products (London, Sept. 2005).
  • EMA, Similar Biological Medicinal Products Containing Biotechnology-Derived Proteins as Active Substance: Quality Issues (London, Feb. 2006).
  • EMA, Guideline on Similar Biological Medicinal Products Containing Biotechnology-Derived Proteins as Active Substance: Nonclinical and Clinical Issues (London, Feb. 2006).
  • EMA website, “Multidisciplinary:Biosimilars” www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000408.jsp&mid=WC0b01ac058002958c, accessed Aug. 5, 2013.
  • FDA, Guidance for Industry: Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product (Rockville, MD, Feb. 2012).
  • FDA, Guidance for Industry: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product (Rockville, MD, Feb. 2012).
  • FDA, Guidance for Industry: Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009 (Rockville, MD, Feb. 2012).
  • FDA, Guidance for Industry: Formal Meetings Between the FDA and Biosimilar Biological Product Sponsors or Applicants (Rockville, MD, Mar. 2013).
  • Patient Protection and Affordable Care Act of 2010, Public Law 111-148 (2010).
  • ICH Q6B Test Procedures and Acceptance Criteria for Biotechnological/Biological Products.
  • FDA, Guidance for Industry: Bioanalytical Method Validation (Rockville, MD, May 2001).
  • K.J. Miller et al., Pharm. Res. 18 (9) 1373-1383 (2001).
  • B. DeSilva et al., Pharm. Res. 20 (11) 1885-1900 (2003).
  • J.M. Smolec et al., Pharm. Res. 22 (9) 1425-1431 (2005).
  • C.T. Viswanathan et al., AAPS J 9 (1) E30-E42 (2007).
  • M. Keley et al., AAPS J 9 (2) E 156-E163 (2007).
  • EMA, Guideline on Bioanalytical Method Validation (London, Jul. 2011).
  • EMA, Guideline on Immunogenicity Assessment of Biotechnology-Derived Therapeutic Proteins (London, Dec. 2007).
  • EMA, Guideline on Immunogenicity Assessment of Monoclonal Antibodies Intended for In Vivo Clinical Use (London, May 2012).
  • FDA, Guidance for Industry: Assay Development for Immunogenicity Testing of Therapeutic Proteins (Rockville, MD, Dec. 2009).
  • A.R. Mire-Sluis et al., J. Immunol. Meth. 289 (1-2) 1-16 (2004).
  • S. Gupta et al., J. Immunol. Meth. 321 (1-2) 1-18 (2007).
  • E. Koren et al., J. Immunol. Meth. 333 (1-2) 1-9 (2008).
  • G. Shankar et al., J. Pharm. Biomed. Anal. 48 (5) 1267-81 (2008).
  • X.Y. Cai et al., Bioanalysis 3 (5) 535-540 (2011).
  • X.Y. Cai et al., Bioanalysis 4 (17) 2169–2177 (2012).

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