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
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.
  • 1.2K
  • 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.
  • 4.8K
  • 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.
  • 796
  • 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).
  • 833
  • 02 Jun 2022
Topic Review
Virus Filter Foulants
The major classes of foulants in virus filtration. This includes irreversible and reversible product aggregates and minor product variants that differ in their charge or hydrophobicity. Product variants arise because mammalian cell-derived biotherapeutics are heterogeneous. The product is defined based on the production process and not on a single molecular species. Product variants with different post-translational modifications can have different hydrophobicity, charge, and conformations. If present, HCP, proteases, and nucleic acids can also foul the virus filter.
  • 417
  • 25 Apr 2022
Topic Review
Mitigation of Virus Filter Fouling
Even though the support structure of the virus filter can function as an inline prefilter, significant fouling is often observed due to the product- and process-related foulants could be present in the feed stream. Standard practice involves the inclusion of a virus prefilter to remove these contaminants. Virus prefilters may rely on one or more mechanisms of action for the removal of foulants.
  • 428
  • 26 Apr 2022
Topic Review
Downstream Processing of Virus Filter
Virus filtration is a single-use, size-based separation process in which the contaminating virus particles are retained while the therapeutic molecules pass through the membrane pores. Virus filtration is routinely used as part of the overall virus clearance strategy. Compromised performance of virus filters due to membrane fouling, low throughput and reduced viral clearance, is of considerable industrial significance and is frequently a major challenge.
  • 1.9K
  • 24 Apr 2022
Topic Review
Nitroaromatic Hypoxia-Activated Prodrugs for Cancer Therapy
The presence of “hypoxic” tissue (with O2 levels of <0.1 mmHg) in solid tumours, resulting in quiescent tumour cells distant from blood vessels, but capable of being reactivated by reoxygenation following conventional therapy (radiation or drugs), have long been known as a limitation to successful cancer chemotherapy. This has resulted in a sustained effort to develop nitroaromatic “hypoxia-activated prodrugs” designed to undergo enzyme-based nitro group reduction selectively in these hypoxic regions, to generate active drugs. Such nitro-based prodrugs can be classified into two major groups; those activated either by electron redistribution or by fragmentation following nitro group reduction, relying on the extraordinary difference in electron demand between an aromatic nitro group and its reduction products. 
  • 433
  • 22 Apr 2022
Topic Review
Theranostic Nanomedicines for Cardiovascular and Related Diseases
Cardiovascular and related diseases (CVRDs) are among the most prevalent chronic diseases in the 21st century, with a high mortality rate. Theranostic nanomedicines can prolong systemic circulation, escape from the host defense system, and deliver theranostic agents to the targeted site for imaging and therapy at a cellular and molecular level. The various nanomedicines for diagnostic and therapeutic applications in CVRDs, including nanomedicine for angina pectoris, myocarditis, myocardial infarction, pericardial disorder, thrombosis, atherosclerosis, hyperlipidemia, hypertension, pulmonary arterial hypertension and stroke are summarized. Presently, discrete non-invasive and non-surgical theranostic methodologies are such an advancement modality capable of targeted diagnosis and therapy and have better efficacy with fewer side effects than conventional medicine.
  • 477
  • 25 Apr 2022
Topic Review
The Surface of the Eye
Drug delivery to the internal ocular structures remains an important and relevant topic owing to the unique immune privileges of the eye which limit the success of systemic injections. The need to prevent and/or treat several common conditions, including age-related macular degeneration, endophthalmitis, retinal degeneration, diabetic retinopathy, and cataracts, has motivated the development of pharmaceuticals that require entry into the eye and extended residency to be most effective. The ocular surface is a surprisingly diverse portion of the eye, consisting of multiple tissues and glands. From a diagnostic standpoint, ocular surface disease may appear on the inside of the eyelid, on the cornea, on the conjunctiva, and in any of the associated glands. The ocular surface also offers an attractive option for drug delivery due to its relative ease of application and minimally invasive approach.
  • 1.3K
  • 24 May 2022
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