Transforming the Biopharmaceutical Development Roadmap

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Advanced analytics and the standardization of single-use systems have transformed bioprocessing

Biopharmaceutical analytical methods have improved significantly since the early 1990s. Techniques and fundamental mechanisms largely have remained the same, but modern analytical tools are delivering better insights into drug-product characteristics thanks to improved reagent quality, method intensification, and automation. Harmonized regulations and the revolutionized role of contract development and manufacturing organizations (CDMOs) also continue to support bioprocess transformations.

Improved Analytics and Standardized Single-Use Equipment
Today’s analytical methods provide high resolutions and deliver reliable results quickly. For example, sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS-PAGE) used to be a laborious process that required practice to cast gels consistently and to quantify results using image analysis. But modern capillary electrophoresis (CE) systems are rapid, robust, and precise. Many biomanufacturers now run mass spectrometry (MS) in house to assess glycan patterns during early stages of cell-line and process development. MS is no longer a characterization method performed late in a drug-development life cycle. With improved analytics, the industry is resolving more critical quality attributes (CQAs) than ever before and applying design of experiments (DoE) to identify and control key process parameters with confidence during development and manufacturing. The time required to optimize processes also has been shortened significantly.

Processing aids have evolved to provide precise and robust performance. Soft gels and size-exclusion chromatography (SEC) have been superseded by high–flow-rate rigid matrices that use highly specific charge or ligands to resolve species precisely. Filtration membranes have tight pore sizes and/or molecular weight cutoffs and can come with functional charge to improve rejection of unwanted species. With today’s bioseparation technologies, biomanufacturers can develop and consistently operate high-yielding processes that generate superior products.

The standardization of single-use equipment is enabling end-to-end bioprocessing solutions. Standardized single-use systems improve productivity, lower contamination risks, shorten turnaround times, facilitate scale-up, and reduce capital investment. Current standard systems come with computerized control that improves the integrity and access to process data.

Combined benefits of modern analytical methods and streamlined manufacturing technologies enable biopharmaceutical companies to allocate resources to clinical aspects of product development. New products can be translated from discovery to proven clinical efficacy quickly. The first three antibody products that I developed at SinoMab took nearly five years to be approved for clinical trials, and we supplemented internal capabilities with quite a few international consultants. Bioworkshops has built a facility with about 10× higher capacity for the same cost and already has completed 10 full chemistry, manufacturing, and controls (CMC) packages in only two years without the need for consultant support.

Harmonized Regulations
Over the past 20 years, international harmonization initiatives and regulatory reforms have changed the development of biologic products dramatically. For my first few investigational new drug (IND) applications in the United States, my team compiled the completed batch records, batch release data, and some general summaries. We also engaged with the Food and Drug Administration (FDA) to agree on the required final content. With adoption of the common technical document (CTD) for submissions, most technical requirements for new products have been codified. Information required in a submission is clearer than it was 20 years ago, and such information can support applications in multiple countries with little modification. Guidelines issued by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) for quality and safety and harmonized good manufacturing practices (GMPs) help manufacturers reduce gaps between major markets so that smaller players can produce investigational materials for multicenter international trials and deliver drug products to more of the global patient population.

The Evolving Role of CDMOs
I thrive on the technical challenges of mastering CMCs for new biopharmaceuticals. For most of the first 20 years of my career in technology and product-development companies, I worked with one or two contract development projects using extra capacity. I enjoyed working on those projects, but they were a sideline for those companies. Over time, I saw a gradual and then dramatic increase in demand for contract services, especially during the rapid increase in the number of antibody products in development. In 2019, I decided the time was right to start a dedicated CDMO, working with a team of like-minded experts who also enjoy the technical challenges of developing biologics.

Since founding Bioworkshops, I have not looked back. Despite challenges brought on by the COVID-19 pandemic, our business has grown faster than we had anticipated. We have expanded to >10,000 L of cell culture capacity and three aseptic drug product filling lines. We are working on about 30 different antibody products per year. I am motivated by this success and look forward to applying my knowledge and experience to help develop many more products.

I see a growing role for service providers that can fully integrate CMC deliverables and take a biologic from sequence to drug-product registration and even on to market. Even as a sponsor with access to my own laboratories and pilot plants, I needed to engage different contract test laboratories to perform analytical testing of such parameters as receptor binding kinetics, glycopattern analysis, and sterility. Twenty years ago, specialist contractors were engaged to develop cell lines using their proprietary technologies that came with a liability for significant future royalty payments. Drug substances and drug products typically were manufactured by different CMOs. Managing multiple third parties was complicated. Even with expert project management, there was a lot of waiting for materials or data to come from different parties.

Out of a drive to improve efficiency and speed — also enabled by standardized and automated analytical and processing systems — many CMOs have expanded capabilities and now provide all the necessary services from one organization. “One-stop shops” (such as Bioworkshops) help clients from early in a product development life cycle. Such CMOs can get involved in developability assessments even before a lead candidate has been selected. After a client provides the sequence of several potential options, Bioworkshops can make high-expressing, stable cell lines, develop analytical methods, lock down a high-yielding process, and start on formulation development to help select a lead molecule. In under a year from starting a developability assessment, Bioworkshops can scale up drug substance manufacturing under GMPs from 200 L to 2,000 L; aseptically fill product into vials or prefilled syringes or for lyophilization, fully characterize materials; and compile CMC dossiers for submission in highly regulated markets. With a strong team of development scientists, the company can handle highly complex molecules such as engineered multivalent antibodies and match exacting target product profiles of biosimilars. Work that used to take 18–24 months from sequence to IND with different specialist suppliers, Bioworkshops now can achieve in eight to nine months. Scale-up risks are reduced, and the need for site-transfer is eliminated.

Thus, the role of CMOs has been revolutionized. They provide integrated contract services from development through to commercial manufacture and deliver high-quality products to patients faster than ever before.

About the CEO
Simon Kwong has been at the forefront of biopharmaceutical development and biomanufacturing for three decades. After graduating with a degree in chemical engineering from the National Taiwan University, he completed a PhD in advanced bioreactor control at the University of Maryland. During a decade in public research in the late 1990s, Kwong designed, built, and operated the first and only FDA-registered and Australian TGA–certified GMP pilot fermentation facility at the Hong Kong Institute of Biotechnology. While leading the expansion of the institute, he secured more than US$22 million of grants and collaborated with the World Health Organization (WHO) and global pharmaceutical companies working on recombinant vaccines, therapeutic proteins, and antibodies.

In 2005, Kwong founded SinoMab, one of Greater China’s first antibody companies, which developed three therapeutic products based on SP2/0 expression systems. In 2010, Kwong cofounded Lonn Ryonn Pharma. In five years, the company established a development and GMP manufacturing facility and advanced nine antibody products from discovery into clinical trials in China, United States, and Australia.

For the past six years, Kwong has applied his experience to CDMO services. He led the start-up of the world’s first KuBio modular environments, which was used in scale-up and GMP manufacture (at 2,000 L) of one of China’s first approved PD-1 products. He cofounded CMAB Biopharma and set up full development capabilities before the company was purchased by WuXi Biologics. Three years ago, Kwong founded Bioworkshops. He has created an international-standard platform for antibody products to complete 15 IND projects per year, from customer support to market launch.

Simon Kwong, PhD, is chief executive officer at Bioworkshops; energize@bioworkshops.com.