With the increased interest and gradual shift of investment from small molecule drugs to biologics and the establishment of several biologics manufacturing companies / biologics CMOs, more than 250 biologic therapies and vaccines have been developed, globally. Notably, biologics have higher success rates than conventional small-molecule drugs owing to lesser off-target toxicity of biologics, which is one of the key reasons of failures in small molecule drugs development. Given the ongoing scientific advancements and the rise of FDA-approved biologics, the pharmaceutical industry seems to be approaching the era of biologics. In fact, biologics are anticipated to play a significant role in shaping the pharmaceutical industry and will eventually serve as an integral part of traditional medicines. Moreover, the exuberant development of biologics has revolutionized the treatment of a range of therapeutic conditions, which has further contributed to the exponential growth in the current demand for biologic therapies developed by biologics manufacturing companies.
Overview of Biologics
Biologics refer to medicinal / therapeutic products that are either manufactured using living organisms or semi-synthesized from biological sources. These are essentially complex biological macromolecules, having high molecular weights, or cell-based products, which are not directly extracted from native biological sources, rather are produced using biotechnology tools and methods. Like all drugs, biologics are regulated by the FDA. They are different from small molecules in terms of their size and complexity.
Chemical drugs are small molecules made up of a limited number of atoms, on the other hand, a biologic molecule is much larger and may have thousands of atoms, making them more complex. Biologics activate certain proteins or cells in your immune system to create specific responses to targets, while many conventional systemic drugs activate the entire immune system in a more generalized manner.
Owing to their large number and different behaviors, biologics can be categorized in a variety of ways. The below given figure provides an illustrative summary of the various types of biologics.
Expression Systems for Biologics
The processes associated with the manufacturing of biopharmaceuticals are complex and require highly sterile and aseptic conditions. This can be attributed to the fact that the production of biopharmaceuticals requires living expression systems. Usually, the desired gene, such as human insulin gene, when inserted into the plasmid of the host cell uses transcriptional and translational machinery of the host to express itself. It is worth mentioning that in vitro gene expression requires a suitable host for the production of a specific gene product. Presently, several expression systems are available for manufacturing of biologics; these include insect, mammalian, microbial and plant expression systems. It is also important to note that the use of different systems is associated with their own set of culturing requirements, advantages and drawbacks.
The below given figure provides an illustrative summary of the various expression systems for biologics.
Different types of expression system for the production of biologics have been mentioned in the following sections:
Insect Expression Systems: Baculovirus is a double stranded DNA (dsDNA) lytic virus that can be effectively amplified in insect cells belonging to the Lepidoptera family. Baculovirus-based expression vectors exploit the ability of a virus from the Baculoviridae family to transfect insect cells. Insect cell lines have been frequently used as recombinant protein expression systems. This method is considered safe since baculovirus cannot infect vertebrates, as its promoters are inactive in mammalian cells.
Mammalian Expression Systems: Mammalian expression systems are known to generate functionally active proteins. However, these systems are characterized by low yields, high production costs and time-consuming cell culturing processes. Commonly used cell lines include Chinese hamster ovary (CHO) cells, baby hamster kidney (BHK) cells. Mammalian cell cultures offer stability and are preferred for long term usage. Transient protein expression in these cell lines is relatively easy and simple; however, scaling up the process has emerged as a considerable challenge over the years.
Microbial Expression Systems: Microbial expression systems are primarily used for production of recombinant proteins. Examples of prominent microbial expression systems are bacteria, fungi, and yeast.
Bacterial Expression Systems: Owing to their rate of replication, bacteria are simple systems that facilitate rapid expression of recombinant proteins. They are easy to culture and are known to generate high yields of recombinant proteins. The most widely used bacterial host system is Escherichia coli (E. coli). Since its genetic and physiological profiles are well characterized, genetic manipulation in E. coli is relatively easy compared to other strains of bacteria.
Fungal Expression Systems: Fungi have been shown to possess the capability to express high levels of different kinds of proteins that are secreted into the extracellular space. This form of production is very beneficial for downstream processing owing to the requirement of minimal recovery steps for the end-product. Further, fungal systems are capable of carrying out post-translational modifications similar to those observed in humans.
Yeast Expression Systems: Simple eukaryotes, such as yeasts, are generally preferred for the production of recombinant proteins and other biologics due to their eukaryotic cellular machinery, low expression time and ease of manipulation. Yeast cells possess the required intracellular factors and proteins that facilitate post-translational modifications. Prominent examples of yeasts that are used as expression systems include Saccharomyces Cerevisiae (S. cerevisiae) and Pichia pastoris.
Plant Expression Systems: The plant in vivo expression system is an inexpensive and convenient system for the large-scale production of recombinant proteins. Over the last decade, several efficient plant-based expression systems have been discovered.
Manufacturing Process of Biologics
The production process of biologics can be categorized into two major stages, namely upstream and downstream processing. Upstream processing includes the production and maintenance of the working microbial expression systems, whereas downstream processing comprises of the various chemical and physical separation steps required to isolate and purify the product from the culture mixture.
The specificity, efficacy and safety-related advantages of biologics have captured the attention of industry stakeholders and consumers. Presently, a variety of biologics is being developed for a wide range of diseases, including those characterized by large target patient populations and rare disease indications, which are typically associated with smaller target patient populations and lower demands. Additionally, novel modalities, including recombinant proteins, vaccines, cell and gene therapies, are growing faster than any other segment of medicine. This has led the biologics to be on the verge of surpassing small molecules in terms of revenues. In this competitive global market, outsourcing has evolved into a viable and profitable business model. Although it is mostly the mid-sized and small players that opt to recruit the services of biologics CMO, some of the larger and more established players are also known to outsource certain aspects of biologic development and manufacturing. In fact, most developers tend to rely on biologics contract manufacturers / biologics contract manufacturing for the development and production of low value / opportunity products, such as drugs for rare indications and biosimilars.
With an experience of over 4 years with Roots Analysis, Jasmeet is adept at generating useful insights from unstructured / structured datasets. As a senior analyst at Roots Analysis, she has assisted several clients across multiple industry verticals within the healthcare domain. These verticals include, contract services, devices / technologies, and drugs / disease indications. Since the findings of the research are aimed at supporting the clients to make thoughtful decisions for their business, she has hands-on experience on competitive landscape assessment, benchmarking, market sizing and forecasting, as well as several quantitative / qualitative / strategic frameworks