Outsourcing Analytical Processes in Biologics Development

Improvements in analytical technologies provide increased capabilities to examine proteins, cell lines, raw materials, and drug product throughout the drug development and manufacturing process. New analytical technologies and regulatory requirements can tax the resources and technical capabilities of drug companies. Contract testing laboratories, which traditionally provided specialized testing services and expertise, are playing new roles in the current biopharmaceutical development market. 

To gain insight on what sponsor companies can gain from outsourcing their analytical processes, BioPharm International spoke with Andrew Bulpin, head of Process Solutions at MilliporeSigma, and Alex Perieteanu, director, biopharmaceutical services; Natalia Belikova, analytical services director; and Bérangère Tissot, general manager and manager Biological Sales; all at SGS Life Sciences.

New technologies and regulatory requirements

BioPharm: Are there new analytical technologies being developed? If yes, how will these impact the industry?

Perieteanu, Belikova, and Tissot (SGS Life Sciences): We have been developing orthogonal analytical tools to work alongside the classic structure and function of biophysical, biochemical, and biological techniques. Hydrogen deuterium exchange with mass spectrometry (HDX-MS) services, in combination with biolayer interferometry (BLI), and surface plasmon resonance (SPR), better equip us to investigate key structural characteristics, or changes that impact biochemical potency.

The pharma and biopharma companies are now at a stage when some of the methods that were deemed fit for characterization only now are entering the quality control (QC) arena:

• Intact molecular weight by mass spectrometry has replaced the sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE)

• Peptide mapping by liquid chromatography-mass spectrometry (LC-MS) is replacing the Western Blot and ultraviolet (UV)-based methods

The multi-attribute methods based on peptide mapping by LC-UV-MS are on the verge of replacing a multitude of the most QC-established methods such as chromatography and capillary electrophoresis.

It is still challenging from a compliance standpoint to bring such complex equipment and software into a QC environment. Additionally, from more of a characterization standpoint, methods that were deemed as being ‘academic’ are now making their way into the biopharma industry, with two-dimensional nuclear magnetic resonance spectroscopy (2D-NMR), HDX-MS, or ion mobility mass spectrometry being among these.

Bulpin (MilliporeSigma): Fluorescent associated cell sorting (FACS) technology has been around for many years, but with the recent miniaturization of the technology, it now allows real-time analysis of cells and cell behavior while interacting with the drug under test. This will change the way we potentially can perform release assays and describe the mode of action of drugs. As miniaturization requires a very small sample for analysis, it allows for monitoring the drug’s activity over a period of time rather than a single point. This provides the kinetic profile of how the drug affects the cells over time.

Another new advancement is the development of inline analytical probes that are maintained within the process that is being tested at the time. Currently there are active research projects to develop these probes offering real-time, in line, analysis. This could fundamentally change the way we release batches of drugs as you would no longer need to take samples and wait for results prior to release. The final result of the batch would be available instantly.

BioPharm: What are the top things companies should be doing when it comes to analytical method development?

Bulpin (MilliporeSigma): Companies should be aware of the changes in technology available to test biopharmaceuticals. For example, newer mass spectroscopy technologies improve sensitivity and specificity.

Companies should also consider the use of software to combine multiple data sets in order to provide an orthogonal approach to assess the safety and efficacy of a product, rather than the current manual processes.

Perieteanu, Belikova, and Tissot (SGS Life Sciences): We have all heard the statement, ‘fit for intended purpose,’ and many laboratories have well established procedures paralleling International Council for Harmonization (ICH) Q2(R1), which defines ‘fit,’ but few have procedures discussing the requirements of ‘intended purpose.’ Arguably, one is of no use without the other. Companies should be taking a holistic look at method development and incorporate key elements of quality by design (QbD).

Defining up front the direction of any program’s development is crucial:

• Know your product: there is a great deal of method development that can start on paper in the preparation of the development

• Understand what is the purpose of the method: define what attributes need to be characterized or monitored relevant to the stage of development the product is at.

A method that is well developed is a method that is efficiently validated and applied to routine testing, so investing the time and money will lead to greater success.

BioPharm: Have there been recent changes in regulatory requirements, either in the United States or internationally, that have impacted how you perform analytical testing and/or method development?

Bulpin (MilliporeSigma): Statistical analysis of data derived from these analytical assays is being re-evaluated and newer techniques are being introduced. For example, the United States Pharmacopeia committees are re-evaluating how the statistical analysis of setting parameters for drug release is determined. This could affect how an assay is developed to ensure that the proper profile is created, such as numbers of batches, replicates, and finally the statistical methods used to assess the data. 

Expertise and capacity

BioPharm: What are the benefits of outsourcing analytical processes?

Bulpin (MilliporeSigma): There are many benefits to outsourcing analytical processes. One benefit is that through outsourcing you have access to the newest and most advanced process technology without having to invest in the technology. Biopharmaceutical manufacturers also have access to skilled, expert resources that are up-to-date in all GMP and validation guidelines and requirements. An outsourcing partner with years of experience and advanced technology will customize and streamline your process, increasing efficiency and reducing cost and risk. 

Perieteanu, Belikova, and Tissot (SGS Life Sciences): The biopharmaceutical landscape continues to rapidly change as new technologies become available, new regulations take effect, and as markets expand. To remain competitive, companies must adapt rapidly, which brings high infrastructure cost, knowledge costs, and risks dilution of focus and internal resources.

The key benefits to outsourcing are the ability to leverage the externally existing infrastructure, expertise, knowledge base, and flexible resources of the provider. These resources include a breadth of instruments and capabilities that are not always possible or feasible to invest in internally. A contract research organization (CRO) is usually proficient in a wide number of techniques, and if they have successfully passed their regulatory inspections, can offer a high level of confidence to sponsors that its processes and procedures are proficient and applicable to a variety of products. A CRO’s cost and timelines can also be managed by contracts and controlled more rigorously than a sponsor’s internal spend can be. 

BioPharm: What changes are you seeing in the industry regarding the outsourcing of analytical services?

Perieteanu, Belikova, and Tissot (SGS Life Sciences): We are witnessing greater demand from clients for integrated services, meeting ever shorter timelines to reduce the development cycle of new drugs, and requests for more complex services such as characterization and analytical similarity.

The biosimilar space continues to grow, and because of a desire to remain lean, rapid, and versatile, there is an ever-increasing number of near virtual companies that have adopted a pure outsourcing model. Being the first to market with a biosimilar stands to reap the greatest reward, and many depend upon this financial model. Analytics are arguably the main cost component in biosimilar development, and because CROs can offer off-the-shelf expertise, platform analytics for characterization, and routine testing, there is considerable time and cost advantage to the outsourcing model. However, for clients requiring analytical guidance, regulatory feedback with regards to analytical methods, risk assessment, or analytical method lifecycle management, bespoke models can be offered that are more than just fee-for-service.

Bulpin (MilliporeSigma): Recently, one trend that has become significant within the industry is the increased interest in understanding the glycan structures in biologic molecules, especially, monoclonal antibodies. New technologies are being explored that have helped with this, including mass spectroscopy and glycan kits. The increasing sensitivity with mass spectrometry allows one to identify possible post-translational modifications due to increased precision. While previous methods of glycan analysis could take multiple runs and lengthy analysis, glycan kits help to expedite glycan detection and identification as well as the three-dimensional structure of the glycans. 

BioPharm: Are biopharmaceutical companies outsourcing their analytical processes more or less than five years ago?

Bulpin (MilliporeSigma): Regulatory requirements for more detailed and technically demanding analysis is driving biopharmaceutical companies to outsource their analytical processes. We have seen a more than 30% increase in outsourcing over the past five years. Development of biosimilars in the mid-2000s has driven the need for sophisticated analytical technologies as clinical trials are unable to differentiate similar molecules in their efficacy. Due to these scientific advances, the innovator molecule development has adopted some of these technologies in describing their molecule’s analytical profile.

Through mergers and acquisition, the CRO industry has changed, creating a new model for outsourcing. While in the past, a company would require multiple providers to complete a full testing profile, companies today can use single-service providers to test the full complement of assays allowing for a broader understanding of their molecules activity. Single-service providers often reduce time and cost by simultaneous testing and the ability to create a cohesive scientific panel of experts.

Perieteanu, Belikova, and Tissot (SGS Life Sciences): The trend continues to be toward consolidated outsourcing. We are increasingly seeing that instead of only using CROs for overflow or niche testing, sponsors are looking to outsource the entire analytical paradigm, by partnering with CROs with robust analytical capabilities mirrored across multiple continents.

BioPharm: Which analytical services are requested most often by bio/pharmaceutical companies?

Perieteanu, Belikova, and Tissot (SGS Life Sciences): Interestingly, it tends to be less about the analytical technique itself, but more about the application of the work being conducted. Applications that lead to patents that can have an impact on patient safety, that provide data on the efficacy, the biosimilarity of the product, and/or ultimately are included in regulatory submissions have certain requirements in terms of their study design and level of quality. Because of the criticality of such applications, you often see those studies being outsourced to CROs.

Bulpin (MilliporeSigma): Bioassays are the most requested analytical services by biopharmaceutical and pharmaceutical companies. This is often due to the complexity of working with these assays. Advanced technology is needed to run bioassays, in addition to a skilled and experienced scientist. Maintaining a laboratory that employs the scientific staff that can accomplish these assays is seldom economically viable for many small- and medium-sized companies, and even sometimes larger pharmaceutical companies.

Also, in order to create the proper in-vitro model for the disease that can measure the efficacy and biological outcome of the test substance, these assays must be completed in a controlled environment to produce a robust and reproducible result. Analytical chemistry identifies the presence of specific structures; however, cell-based assays are looking for the mode of action in order to mimic the effect that will be seen in humans. 

Analytical testing challenges

BioPharm: What challenges in analytical testing have developed in recent years? 

Perieteanu, Belikova, and Tissot (SGS Life Sciences): As the biopharmaceutical industry matures and diversifies, we are beginning to see more and more cell, gene, and other advanced medical therapies alongside the more traditional vaccine, enzyme replacement, and immunotherapy products. The analytics and the analytical strategy required for each continue to develop and mature as the industry and the regulators better understand and define the controls and monitoring required to ensure all critical product quality attributes are met. Having the right knowledge base and analytical tools available is essential for companies entering these markets.

Bulpin (MilliporeSigma): Today, regulators are emphasizing the use of quality by design for developing new molecules and design of experimentation (DoE) when a new analysis is applied to a product. These systematic methods are novel to many people working in the industry and are difficult to apply in some instances. To answer these difficult questions, one must start looking at using multiple forms of analysis to answer in depth questions that cannot be obtained from a single assay in isolation. Using information from binding kinetics, analytical markers, as well as biological activity, paints a full picture of the molecule’s design and function. There are now some software packages that specifically address DoE. While these can be particularly useful with analytical chemistry, sometimes the bioassays are still difficult to apply the DoE techniques, which still need to be resolved. MilliporeSigma has identified solutions to these difficult questions in order to move through the drug development process and is actively talking to regulators about the application of these technologies.

BioPharm: How has the surge in biologics affected the analytical services you provide?

Perieteanu, Belikova, and Tissot (SGS Life Sciences): In recent years, one focus of note was the diversification and enhancement of our structure and function analytical capabilities, which include development of services such as HDX-MS, BLI, SPR, and upgrading of our flow cytometry capabilities. In the coming years, we anticipate multi-faceted growth both in the traditional products, biosimilars, and in advanced medical therapies. Our goal is to maintain an industry lead, and to ensure that the one-stop shop of today expands to be the one-stop shop of tomorrow.

Article Details

BioPharm International
Vol. 31, No. 4
April 2018
Pages: 36-40

Citation

When referring to this article, please cite it as S. Haigney, "Outsourcing Analytical Processes in Biologics Development," BioPharm International 31 (4) 2018.