spacer
home > ebr > summer 2016 > winning the race
PUBLICATIONS
European Biopharmaceutical Review

Winning the Race

The EMA was the first regulatory body to implement an approval procedure to authorise subsequent versions of previously approved biologics (innovators), termed “similar biological medicinal products”, or biosimilars. This process is based on a thorough demonstration of “comparability” of the “similar” product to an existing approved product (1). The EMA has granted marketing authorisation for 20 biosimilars under this procedure (see PDF for Table 1). In the US, the FDA has finalised its long-awaited draft guidance on biosimilars (2,3,4), providing a regulatory framework for the approval of a biologic demonstrated to be similar to an already marketed product. To date, the FDA has approved just one biosimilar – Zarxio (filgrastim-sndz).

Accelerated Development


With patents for many biologic blockbusters expiring soon, estimates of the potential market size for biosimilar drugs continue to be adjusted upward by quantum leaps. These events have resulted in an acceleration of biosimilar development in the EU, Asia and the US. As patents on popular biological medical products begin to expire, drug manufacturers are competing to get their biosimilars to market in a timely, cost-effective manner. Table 2 (see full PDF) lists the key targets of biosimilar developers. A vital component to being the first to market is the ability to efficiently navigate the vast analytical testing requirements for the development of biosimilars. Regulators demand extensive testing and characterisation of the biosimilar to show that it is highly similar to the reference product.

For biosimilars, the extent of characterisation determines the need for additional nonclinical and clinical studies, thus shifting more analytics to the front of the development process and escalating its importance. Therefore, this evolution in the biopharmaceutical industry involves many players, but none more dramatically than a biopharmaceutical product testing laboratory. Some important strategies for streamlining the required testing discussed here include comprehensive characterisation using mass spectrometric approaches and validated bioassays, efficient development and validation of robust methods, simultaneous installation of methods into multiple testing facilities, and access to extensive capacity for process validation plus stability and release testing.

Characterisation Techniques

As stated earlier, intensive characterisation is crucial to the success of a biosimilar candidate. Mass spectrometry (MS) coupled with liquid chromatography (LC) is an extremely powerful characterisation tool for these large, complex biomolecules. Contemporary top-down and middle-up approaches using LC-MS and various novel separation techniques can be implemented to measure primary structure, including amino acid sequence, intact masses of the whole protein and associated subunits or domains.

Similarly, the current state of classical peptide mapping – using LC and tandem mass spectrometry (LC/MS/MS) with scan-dependent acquisition – speeds analysis and provides information on post-translational modifications, glycosylation and disulfide mapping in an efficient manner. A full understanding of glycan structure is critical to a well-characterised biosimilar. Historically, glycoprofiling is a time-intensive and tedious analytical undertaking. However, novel labelling schemes that are sensitive to both detection by fluorescence and MS can be utilised for thorough and efficient glycoprofiling. Other characteristics of the biosimilar that are typically studied and compared to the innovator include charge and size heterogeneity by electrophoresis, secondary and tertiary structure by circular dichroism, thermal stability by differential scanning calorimetry, aggregation by size exclusion chromatography, and a variety of other techniques.

The 2015 FDA Draft Guidance on ‘Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein Product to a Reference Product’ (3) also acknowledged other methods able to further characterise 3D conformation of a protein, which plays an important part in its biological function. Among these, multi-dimensional nuclear magnetic resonance (NMR) spectroscopy can help define tertiary protein structure and, to varying extents, quaternary structure, and can add to the body of information supporting biosimilarity. NMR is a structural tool that is inherently multiplexed. It has a demonstrated ability to rapidly assess protein folding, characterise glycans and determine protein structure. This final application is particularly important as proposed US guidance calls specifically for NMR structural characterisation for biosimilar molecules. It is most suited for small protein therapeutics, and can as such be used to support biosimilarity demonstration – leading to a high level of structural resolution and details. Nevertheless, applying NMR fingerprinting approaches, even on very large biomolecules such as monoclonal antibodies, can also be considered. Indeed, the maps that can be derived and compared between innovator and biosimilar products are, in principle, direct fingerprints of the primary sequence and folding of the protein.

In addition to biochemical assays, biological potency testing is another critical aspect of biosimilar product characterisation. A fully developed/validated biopotency assay that speaks to the mechanism of action of the product and uses the innovator product as the reference standard allows direct, head-to-head comparison between the biosimilar products and its innovator version. In general, a cell-based potency assay is preferred by the regulatory agents, since it is considered more physiologically relevant. It is of importance to note that in some cases, post-marketing clinical research has provided clear evidence that additional mechanism of action(s) beyond what was originally focused on during innovator product development is crucial to their clinical efficacy. Correspondingly, the bar on biopotency testing has been raised for the respective biosimilar products to include multiple assays that reflect all known mechanism of action(s) in order to provide a more comprehensive comparability assessment.

Method Implementation

Methods that exist for innovator products can be difficult to obtain, or can lack sufficient detail for quick method establishment in the laboratory. Therefore, biosimilar programmes tend to be method development-intensive, and it is critical to utilise testing labs that have built up a strong knowledge base around these biopharmaceutical products. Further, many biosimilar developers plan to market and release drug products in various geographic locations (in both the US and EU), and will therefore need analytical testing support in multiple testing facilities.

The traditional system is to develop and validate methods in one lab and then perform method transfer to a second. An alternative approach to accelerate method installation at multiple sites is to execute co-validation of methods. Under a well-written protocol, validation activities can be performed at two labs. This allows for methods to be installed simultaneously in both facilities, thus greatly expediting the process and decreasing the cost.

When planning for method implementation, potency testing stands out as the most challenging and time-consuming task. Due to the complexity of the assay, the technical expertise of the testing lab in particular is of paramount importance, but many improvements in potency assay approaches have been made during the last five to 10 years. Regulatory scrutiny and general expectations on potency assay testing have also increased dramatically. Therefore, identifying a partner testing lab that has demonstrated experience and regulatory knowledge in the relevant biosimilar product(s) is critical to the successful and timely implementation of potency testing.

Choosing a Partner

Careful consideration must be given when choosing a testing lab partner as programmes move into stability and release testing, as well as process validation activities. Several key points to consider include capability, capacity and project management.

Biosimilar programmes require quite a wide variety of testing and expertise. There is a regulatory expectation that key characteristics linked to critical quality attributes are measured with orthogonal methods, so multiple methods may be used to measure purity or other aspects. Therefore, the testing lab must have the capability to perform a wide array of physiochemical, microbiological and biochemical assays. These activities and assays encompass a broad range of skill sets, expertise, equipment and instrumentation. In conjunction with the capabilities, it is imperative that the testing lab has adequate capacity. Stability and release studies and process validation have the potential to produce many samples that need to be tested in a relatively short time-frame. Therefore, redundancy of specialised equipment and trained staff must be considered.

Lastly – and just as important as capability and capacity – strong project management is paramount. Large biosimilar programmes can be logistically challenging and require a tremendous amount of planning, forecasting, scheduling, follow-up and communication. Regular calls and meetings between the sponsor and testing lab are crucial. A well-run meeting should be agenda-driven and followed up with minutes and action items in a timely manner. Key discussion topics might include: planning for upcoming pulls or process validation submittals; sample status; out-of-specification and ‘anomalous’ results; investigations; and reference standards management. A proficient project manager must be able to effectively interface with the various testing labs, quality assurance, stability storage, contract manufacturers and the biosimilar sponsor. Therefore, the testing lab should have a proven track record in managing these types of programmes.

Ensuring all of these components of testing are performed efficiently, while maintaining a high level of quality, will greatly improve the chances of success of a biosimilar programme.

References
1. EMA, Guideline on similar biological medicinal products, CHMP/437/04 Rev 1, 2014
2. FDA, Guidance for industry: Scientific considerations in demonstrating biosimilarity to a reference product, 2015
3. FDA, Guidance for industry: Quality considerations in demonstrating biosimilarity of a therapeutic protein product to a reference product, 2015
4. FDA, Biosimilars: Questions and answers regarding implementation of the Biologics Price Competition and Innovation Act of 2009, 2015

Read full article from PDF >>

Rate this article You must be a member of the site to make a vote.  
Average rating:
0
     

There are no comments in regards to this article.

 You must be a member of the site to make a comment.
spacer
Dr Jon S Kauffman is Senior Director of Biochemistry, Method Development & Validation, Protocol Development and Technical Writing at Eurofins Lancaster Laboratories. His teams are responsible for developing and validating methods and performing analysis of clinical and commercial samples for stability and release purposes. Jon's key roles are to interface with clients and his team to ensure positive project outcomes by maintaining compliance and a high level of quality. He earned a doctorate in Chemistry from the University of Delaware and has over 25 years’ experience in the analytical testing field.

Dr Weihong Wang
is Technology Development Manager for Eurofins Lancaster Laboratories’ Molecular and Cell Biology group. Serving as a subject matter expert and direct technical contact to assist clients with testing needs, Weihong has 15 years of experience developing and characterising biopharmaceutical products and has extensive experience with enzyme-linked immunosorbent assays and cell-based assays. She has earned a PhD in Cell and Molecular Biology from Brandeis University and completed postdoctoral research at Harvard Medical School.

Dr Frederic Girard is founder and Managing Director of Eurofins | Spinnovation Analytical BV. Spinnovation delivers analytical R&D and QC testing services to support Small Molecules CMC and Biologics Upstream and Downstream Processing activities. Frederic is responsible for the management of operations and is also strongly involved in sales and business development activities. He earned a Master’s degree in Chemistry with a minor in Biology, and a PhD in Biophysical Chemistry from the University Orleans in France. Frederic has over 15 years’ professional experience in the analytical R&D, with many years dedicated to NMR spectroscopy.
spacer
Dr Jon S Kauffman
spacer
spacer
spacer
Dr Weihong Wang
spacer
spacer
spacer
Dr Weihong Wang
spacer
spacer
Print this page
Send to a friend
Privacy statement
News and Press Releases

Drive for generics sees Korea increasingly attractive to international pharma

Amsterdam, 31st July 2019: Already home to more than 40 pharmaceutical multinationals, Korea is on course to become a global biotech and pharmaceutical hub by 2025, driven by the surge of international partnerships, biosimilars, an expansion in the export of finished formulations and a robust generics market.
More info >>

White Papers

Stripping the confusion out of PVC curtains... and a new seat range.

Teknomek Ltd

With the ever-growing trend towards modularisation of clean rooms and laboratories; Teknomek have responded with a new range of PVC strip curtains, suitable for use in environments where maintaining clean airflow is critical. This new PVC curtain range includes specialist perforated and electrostatic discharge alternatives to the standard options of clear and polar (-25oC) versions.
More info >>

 
Industry Events

SAPHEX 2019

23-24 October 2019, GALLAGHER CONVENTION CENTRE, 10 RICHARDS DRIVE, HALFWAY HOUSE, MIDRAND, 1685, SOUTH AFRICA

SAPHEX 2019 will be held on the 23rd-24th October at the Gallagher Convention Centre, Johannesburg, South Africa.
More info >>

 

 

©2000-2011 Samedan Ltd.
Add to favourites

Print this page

Send to a friend
Privacy statement