Continuous Processes: Disposables Integrate Upstream and Downstream Processing – Featured Report

15-5-FR-Coverby Cheryl Scott, Senior Technical Editor, BioProcess International

Continuous processing is pretty much a “given” in many industries — even the larger pharmaceutical industry that makes synthetic small-molecule drugs. But the concept has only just begun to make inroads with biomanufacturers, who have until recently worked mainly in batch or fed-batch mode. Single-use technologies largely have enabled them to consider the possibility of process intensification and going continuous. In support of this month’s featured report, I asked contributor Margit Holzer, PhD (scientific director at Ulysse Consult S.a.r.L in Luxembourg) a few general questions on the topic.

One question often asked of perfusion and other continuous culture approaches is “How do you define a batch?” Some experts say it isn’t even necessary to do so. Others say you can describe batches in terms of time. What do you think?

HOLZER: It is important to recall that traceability of the whole batch history of a drug substance or product is absolutely necessary for CGMP production. So there is no choice. A batch also needs to be defined for continuous upstream operations. This becomes especially crucial during investigations or product recalls. In the case of continuous production, a batch may correspond to a defined fraction of production.

The batch size of a continuous upstream process can be defined, for example, by a fixed quantity (e.g., volume, mass, or activity units of product) of harvested product; the amount produced within a fixed time interval (e.g., hours of production, residence time) between harvests; or the number of cell generations or doubling times to be produced, collected, and further treated in downstream processing as one batch. In addition, a minimum titer and/or viability and/or other quality requirements can be specified as acceptance criteria for pooling with the harvested product to assure batch homogeneity. For all those cases, downstream processing capacity must be in line with the harvested quantity of material.

What’s the most challenging part(s) of downstream processing to do continuously? Continue reading “Continuous Processes: Disposables Integrate Upstream and Downstream Processing – Featured Report”

Who are the competent biomanufacturers?

by Nick Hutchinson

Once upon a time, this seemed like a very easy question to answer. Engineering companies designed facilities with stainless steel equipment to the user requirement specifications of their biomanufacturing customers. These biotech companies then operated the facilities, producing quantities of product to supply the market. They understood these products, having developed them in-house, and had designed, characterized and scaled-up the required bioprocess. They put in place the quality systems necessary to ensure the safety of their patients. In short, these biopharma companies were vertically integrated with competencies in developing, producing and marketing their products in a tightly regulated market. To better serve their customers they invested in manufacturing sciences leading to process innovations that lowered costs, increased throughput and improved product quality.

Leading biopharmaceutical firms still see biomanufacturing as a core competence. Amgen, to give one example, proudly states in its 2016 Annual Report that the company’s “long record of delivering reliable supplies of high-quality medicines with improving efficiency is a source of differentiated competitive advantage”.

Continue reading “Who are the competent biomanufacturers?”

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.

Continue reading “Biomanufacturing networks and the next generations of production facilities”

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.

Continue reading “Continuous or intensified bioprocessing? The gold standard for improved productivity”

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