Summary

The advent of biopharmaceuticals in current medicine brought enormous benefits to the treatment of life-threatening human diseases (e.g., cancer, diabetes and neurodegenerative disorders), and improved the well-being of many people worldwide. The global portfolio of these therapeutic products include proteins and antibodies, nucleic acids, and cell-based products, and continues to expand at a rapid pace - approvals in the period 2015-2018 essentially double the typical five-yearly historical approval pace (G. Walsh, Nat. Biotechnol., 36:1136-1145, 2018) -, representing a significant share of the entire market of pharmaceuticals.

Innovation in the (bio)pharmaceutical industry has been driven towards the development of cost-effective manufacturing processes, envisaging the delivery of products in high quantity, with superior quality (purity), and high specificity, with the ultimate goal of benefiting patients. Progress in this direction have resulted from the application of novel technologies in the upstream stage (high-throughput, single-use devices, statistical optimization of media and fermentation conditions, QbD, and continuous processing), while at the downstream level, chromatography has evolved through the development of new resins and ligands, coupled with advances in process modelling, operating and control strategies.

An emerging trend is the application of alternative solvents such as ionic liquids and deep eutectic solvents, in which their structure and physicochemical properties can be tuned to address unmet needs in (bio)pharmaceutical research. These compounds may be derived from natural and reneawable sources and hold great promise in the development of efficient, sustainable and cost-effective biopharmaceuticals purification processes.

This Entry Collection aims to provide the latest progresses achieved in pharmaceuticals bioprocessing. We welcome submissions of original research, comprehensive reviews and perspectives, including, but not limited, to the following fields:

- Upstream processing (genetic engineering, systems biology, difficult-to-express proteins, expression conditions, Quality by Design approaches, process analytical technologies);

- Chromatographic purification methods (process modelling and control, continuous bioprocessing, design and characterization of resins and ligands, new formats);

- Alternative purification methods (aqueous biphasic systems, filtration, crystallization, precipitation);

- Application of neoteric solvents in upstream and downstream stages;

- Analytical characterization of biopharmaceuticals (stability, post-translational modifications, biological activity, immunogenicity); 

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Entries
Topic Review
G Protein Coupled Receptor 158
G-protein-coupled receptors (GPCRs) remain one of the most successful targets for therapeutic drugs approved by the US Food and Drug Administration (FDA). Many novel orphan GPCRs have been identified by human genome sequencing and considered as putative targets for refractory diseases. Of note, a series of studies have been carried out involving GPCR 158 (or GPR158) since its identification in 2005, predominantly focusing on the characterization of its roles in the progression of cancer and mental illness. However, advances towards an in-depth understanding of the biological mechanism(s) involved for clinical application of GPR158 are lacking.
  • 1.2K
  • 28 Apr 2022
Topic Review
The Development Perspective and Recommendations of Biosimilars
Making biosimilars accessible means reducing their cost of development, which is currently at around USD 100–200 million, keeping small and medium-size companies out of play and leaving most current biosimilars in the hands of big pharma. How this cost breaks down is an interesting subject.
  • 869
  • 27 Apr 2022
Topic Review
Clinical Efficacy and Safety, Interchangeability of Biosimilars
Clinical safety and efficacy studies add substantial cost and time to the approval of biosimilars. However, this argument will have little weight if these studies were able to add additional value over and above the rest of the testing. Interchangeability is a legally defined path in the US biosimilar guidance.
  • 776
  • 27 Apr 2022
Topic Review
Pharmacology of Biosimilars
Testing in animals is an old routine used for new drugs to avoid serious toxicity to humans. However, biological drugs may not always show a pharmacologic response in animal species; thus, the toxicity is an extension of the pharmacological response for biological drugs. Clinical pharmacology comparisons comprise the most relevant testing to support the biosimilarity of a biosimilar candidate. When a novel drug is developed, PK/PD testing is carried out on many volunteers to understand the diversity of disposition in terms of gender, age, and genetic distribution.
  • 1.1K
  • 27 Apr 2022
Topic Review
Analytical Assessment of Biosimilars
The analytical assessment includes testing physicochemical and functional attributes to establish a claim of biosimilarity. How closely a biosimilar candidate should match the reference product will remain questionable since a reference product is approved based on whatever quality attributes it presents; a biosimilar candidate, on the other hand, must match these quality attributes, even if the reference product’s attributes are not the most desirable.
  • 2.4K
  • 27 Apr 2022
Topic Review
Regulatory Pathway of Biosimilar
While most biosimilars have rigidly followed the WAC pricing of 3–30% below the reference product in the US, we can anticipate significant price drops in the future. Since the US market represents 40% of the world market, price drops in the US are pivotal in presenting the overall benefits of biosimilars. In the EU, the pricing of biosimilars is a regional issue, presenting a range of 30 to 70% of market share and price drops of up to 85%, with Norway, Denmark, and Italy leading the reductions. The success of biosimilars in Europe was due to them achieving widespread acceptance by payers, providers, and patients as an integral part of medicine through an extensive program involving preparing stakeholders, investing in evidence generation (e.g., the NorSwitch trial), and introducing incentive models to share payer savings with hospitals. A key component of this success was forced switching, which is not possible on legal grounds in some countries and due to commercial interest in others.
  • 1.7K
  • 27 Apr 2022
Topic Review
The Coming of Age of Biosimilars
The first biosimilar, Sandoz’s Omnitrope  (human growth hormone), was approved in 2006 by both the FDA and EMA; it was approved by the FDA under the 505(b)(2) generic product legislation and by the EU as a biosimilar. Later, Sandoz received the first licensing of Zarzio/Zarxio (filgrastim) in 2015; this was the first biosimilar product approved under the 351(k) BLA legislation in the US. Biosimilars have come of age from 2005 to the present, with 84 approvals in the EU and 35 in the US, representing almost 90% of the world market. While the acceptance of biosimilars in the US is catching up with that in the EU, the cost benefits remain elusive due to the high development barrier and complex distribution system involved, mainly in the US. In the EU, the cost of biosimilars has already dropped 70% or more, and interchangeability is a routine in some European jurisdictions, unlike in the US, where a separate regulatory approval is required.
  • 2.6K
  • 27 Apr 2022
Topic Review
Levetiracetam Mechanisms of Action
Epilepsy is a chronic disease that affects millions of people worldwide. Antiepileptic drugs (AEDs) are used to control seizures. Even though parts of their mechanisms of action are known, there are still components that need to be studied. Therefore, the search for novel drugs, new molecular targets, and a better understanding of the mechanisms of action of existing drugs is still crucial. Levetiracetam (LEV) is an AED that has been shown to be effective in seizure control and is well-tolerable, with a novel mechanism of action through an interaction with the synaptic vesicle protein 2A (SV2A). Moreover, LEV has other molecular targets that involve calcium homeostasis, the GABAergic system, and AMPA receptors among others, that might be integrated into a single mechanism of action that could explain the antiepileptogenic, anti-inflammatory, neuroprotective, and antioxidant properties of LEV. This puts it as a possible multitarget drug with clinical applications other than for epilepsy.
  • 9.1K
  • 27 Apr 2022
Topic Review
Processing of Fab Fragments in E. coli
Monoclonal antibody fragments (Fab) are a rising class of biotherapeutics and their production has been optimised using coexpression of molecular chaperones such as DsbC or DnaK–DnaJ–GrpE, as well as strain engineering for post-translational modifications such as disulphide bridging. Different media systems such as EnBase and combining nitrogen source supplementation with low-temperature cultivation have resulted in improvement in cell integrity, protein expression, and protein refolding. The recovery of native proteins from insoluble inclusion bodies can be improved by adjusting refolding conditions, as well as by incorporating multimodal and affinity chromatography for achieving high product yields in purification.
  • 2.0K
  • 27 Apr 2022
Topic Review
The Coming of Age of Biosimilars: Perspective
The first biosimilar, Sandoz’s Omnitrope (human growth hormone), was approved in 2006 by both the FDA and EMA; it was approved by the FDA under the 505(b)(2) generic product legislation and by the EU as a biosimilar. Later, Sandoz received the first licensing of Zarzio/Zarxio (filgrastim) in 2015; this was the first biosimilar product approved under the 351(k) BLA legislation in the US Many firsts were to follow in the US: the first mAb (bevacizumab), the first pegylated cytokine (pegfilgrastim), the first ophthalmic biosimilar (ranibizumab), and the first two interchangeable biosimilars (insulin glargine and adalimumab). The US also approved the first biosimilars without clinical efficacy testing (filgrastim, pegfilgrastim, and erythropoietin alfa).
  • 1.4K
  • 02 Jun 2022
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