Biomanufacturing networks and the next generations of production facilities

by Nick Hutchinson

Last month, speakers from UCB Pharma, Biogen Inc and Amgen were describing next generation processes development – platforms, products and plants during the opening plenary session of the BioProcess International European Summit. The industry, it would appear, is continuing to evolve its approach to manufacturing operations in response to changing market conditions and innovations in production technologies.

In the past, monoclonal antibodies typically made up a significant proportion of company’s pipelines. Recently, however, these pipelines have become more diverse and so the manufacturing networks of large biopharma companies need to be “modality agnostic”. This diversity extends beyond just the type of molecule being produced but also extends into the dosing regime, such that drug product facilities must be suitably adaptable.

Market Uncertainty

Increasing drug potencies and specificities are leading to a downwards trend in the production volume requirements for a given product. However, at the same time, products are nowadays expected to be supplied to global markets rather than a handful of geographical regions. Uncertainly in forecasted demand is growing as firms extend their reach into previously unchartered markets and the industry become more competitive. Biopharmaceutical companies are placing greater emphasis on developing agile manufacturing networks and larger firms see operations functions as a key value driver to be integrated into corporate goals.

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Biosimilars: Technical and Regulatory Challenges Featured Report

15-4-FR-Coverby Cheryl Scott, Senior Technical Editor, BioProcess International

At least one innovator company has embraced the concept of biosimilars wholeheartedly, calling it “our next chapter in healthcare” in a 2016 report. That publication cites product characterization, preclinical studies, nomenclature, reimbursement, and regulatory pathways as the primary challenges facing companies in biosimilar development. (Note: See Amgen’s 2017 biosimilars report here.) For our own featured report on biosimilars this month, we asked the contributors about those topics. The answers below come from Bruno Speder (head of clinical regulatory affairs at SGS) and Mario DiPaola (senior scientific director at Charles River Laboratories).

Product Characterization: What is the most challenging aspect of biosimilar characterization? How are companies obtaining originator samples to compare against?

SPEDER: One major challenge in developing biosimilars is to obtain sufficient originator product for characterization testing in both the preclinical and clinical development phases. The supply of originator product is very closely monitored by the manufacturers of those products because they seek to slow down the development of biosimilars. So this can be a difficult task. Originator product samples usually are obtained through specialized distributors.

Preclinical Studies: Can nonclinical/animal studies aid in supporting extrapolation of indications? Continue reading “Biosimilars: Technical and Regulatory Challenges Featured Report”

Continuous or intensified bioprocessing? The gold standard for improved productivity

by Nick Hutchinson

Process intensification and continuous biomanufacturing continue to attract a lot of interest within the biopharmaceutical industry as method that can increase productivity and make the most efficient use of production assets.

I interviewed Dr Gerben Zijlstra, formerly of DSM Biologics and the first named inventor on the patent for the XD® (Concentrated Fed-Batch) Technology. He now designs and implements continuous process platforms for biomanufacturers around the world for Sartorius Stedim Biotech.

What is the difference between intensified and continuous bioprocessing?

GZ: A fully continuous biomanufacturing process consists of interconnected continuous unit operations, without intermediate holding tanks, through which the product travels into the containers for Drug Substance in a seemingly constant flow.

Continuous unit operations represent an extremely intensified form of processing and have short downtimes relative to the amount of time they are used for production. A fully continuous biomanufacturing process might have a perfusion bioreactor coupled to a multi-column chromatography capture step, followed by flow-through virus inactivation, multi-column intermediate purification, a flow-through membrane adsorber polishing step, continuous virus filtration and a final ultrafiltration step operated in continuous mode. K.B. Konstantinov and C. Cooney have written an excellent review on this subject.

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New analysis methods are needed for sub-visible particles in drug development

At Vironova we’re in the business of electron microscopy-based digital image analysis of sub-visible particles to provide objective and meaningful information during process development and quality control of vaccines and drug/gene delivery systems.

In current advances in drug-delivery, production of vaccines and drug formulation there are many applications for nano-sized particles such as liposomes and virus particles, and these constitute fast growing and promising technologies for new treatment development.

Continue reading “New analysis methods are needed for sub-visible particles in drug development”

Understanding nanoparticle based processes and products

Josefina Nilsson, Head of EM services at  Vironova, is speaking on the characterization of gene therapy vectors, VLPs and whole viruses at BioProcess International Europe 2017. We asked her about nanoparticle based processes and products.

Why are modern techniques needed for a better understanding of nanoparticles in process development and production?

‘There is a need to link product understanding and process control during biopharmaceutical development. There are many parameters to track such as aggregation, changes in morphology and integrity as well as purity of particles/recombinant proteins/monoclonal antibodies. Sub-visible particle characterization is essential when comparing sample quality at different formulations or after various purification steps to achieve final product quality and stability.

We need methods that provide sufficient resolution and detailed information and that are cost-effective and adaptable to the regulatory requirements for routine drug development.

The combination of visual proof and metric values is not achievable from the currently used indirect methods like dynamic light scattering, nor is it feasible with conventional electron microscopy mainly due to the very long hours of manual work required.’

What are the challenges around regulatory expectations for nanoparticle based processes and products?

‘Methods and measurements need to be robust, reproducible, traceable and of course objective. Nanoparticles need to be visualized at high resolution to assess their purity and integrity, amongst other parameters.

The MiniTEM™ system from Vironova precisely provides the high-resolution visualization (through transmission electron microscopy) required. Automation enables accumulation of the large amount of data and analysis of the statistically relevant number of particles that are needed to produce objective measurements.

Having access to this bench-top, easy to use technology on-site and being able to routinely check samples at different phases during development omits the risk of moving too far down process design routes that will not result in desired final product quality.’

Josefina Nilsson is speaking on Day 1 of BioProcess International Europe 2017. Her talk – Characterization of Gene therapy vectors, VLPs and whole viruses from pre-formulation through process development to final manufacturing – is part of the Vaccine Manufacturing stream on 25th April in Amsterdam. To find out more and register for a pass to join 800+ bioprocessing decision makers at BPI Europe, visit the website

BPOG Five-Year Vision for Single-Use Technologies

Single-use technologies (SUT) for biomanufacturing, otherwise known as disposable technologies, have the potential to transform the industry through more cost effective solutions and solve crucial manufacturing and compliance problems. Today, suppliers have made great advances in SUT, but the vision of better, faster and lower-cost operations has not been fully realized.

Over the past two years, the BioPhorum Operations Group has been painstakingly developing best practices for SUT and work streams for extractables and leachables, user requirements and change notifications are advancing and improving the implementation of SUT. Collectively, these efforts represent thousands of man-hours and pool the knowledge and real-life experiences of many of the leading biomanufacturers embracing this technology. But much more is on the horizon.

BPOG and its member companies are developing a five-year vision for SUT, targeting a selection of SUT and auxiliary systems that are critical to ensure that SUT are a mature and established technology for biomanufacturing.

Read the full report on the American Pharmaceutical Review.

Ken Wong, Deputy Director of Process Technology at Sanofi, is presenting on this report  at BioProcess International European Summit. Join 800+ bioprocessing decision makers at the two-day event in Amsterdam on 25-26 April 2017 – find out more and register here

Efficient Integration of Single-Use Equipment During Capacity Expansion Projects

By Nick Hutchinson

More than ever before, biopharmaceutical companies are able to establish their own in-house biomanufacturing capabilities. The adoption of single-use technology has reduced the need for expensive utilities systems and large manufacturing footprints. The inherent flexibility of this technology is allowing firms to connect steps in the production process with relative ease and without the need for fixed stainless steel pipework. Upfront capital costs have diminished and although operating costs remain, they are incurred only when the success of a drug candidate or licensed product warrants further production. Thus, single-use technologies provide a means to mitigate the risk of wasting large capital expenditures in the event a molecule is unsuccessful in the clinic or on the market.

Good engineering practices are key

Single-use technology is available for nearly every step in a biopharmaceutical manufacturing process below a certain scale of production. Biologics such as monoclonal antibodies and viral vaccines can be produced using processes in which the entire product, media and buffer flow-paths are disposable. However, companies attempting to install or expand new biomanufacturing capacity should be mindful that they should follow good engineering practices to maximize the probability of success. Despite the ease with which firms can install single-use capacity, relative to traditional stainless steel projects, this can nevertheless lead to an insufficient consideration of how firms should integrate single-use equipment with other steps in the process chain. The overlooking of proper integration can lead to incorrect equipment sizing, poor equipment design or an incomplete solution being developed. This can result in process failures, delays and the need to perform costly engineering rework.

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