04/17/2024 | Press release | Distributed by Public on 04/17/2024 08:31
The recent introduction of new drugs in the areas of diabetes, obesity, and cardiovascular disease have greatly increasedthe demand for manufacturing of polypeptides Inturn, rapidly increasing commercialization of peptide drugshas driven an industrial intensification in peptideAPImanufacturing pushing to meet quality, efficiency,costand volume criteria.
For commercial-scale peptide API manufacturing, there are in principle two predominant production methodologies: synthetic or recombinant.
Both approaches offer some distinct advantages and face unique challenges, essential for stakeholders in the pharmaceutical industry to understand when selecting the most appropriate production strategy. Here we want to take a look at current state-of-the-art, strengths and weaknesses of each approach, and where the future is heading.
Recombinant peptide synthesis is a biotechnological process that involves the production of peptides using genetically engineered organisms such as bacteria, yeast, or mammalian cells. In this method, the DNA sequence encoding the desired peptide is inserted into the genetic material of a host organism. This modified DNA, typically incorporated into a plasmid or other vector, instructs the host organism's cellular machinery to produce the peptide as it grows and divides.
During recombinant synthesis, the host organism translates the recombinant DNA into the peptide chain, often with the capability to perform post-translational modifications, which are chemical changes made to the peptide after it has been synthesized. These modifications can include phosphorylation, glycosylation, and the formation of disulfide bridges, among others, which are crucial for the functionality of many biologically active peptides.
The peptides produced are then harvested from the culture medium or cell mass and purified through various biochemical techniques to remove any biological contaminants and unwanted byproducts. This method is particularly useful for producing large quantities of peptides and is favored for its ability to naturally incorporate complex peptide structures and modifications that are difficult to achieve through synthetic chemical methods.
The cost-effectiveness for large-scale production and the small waste footprint and sustainable processes will benefit from the increasing market demand.
With technological advancement, it is to be expected that challenges around lengthy development cycles and up-front costs, as well as the limited ability to accommodate modifications, will be smaller in the near future.
Synthetic peptide synthesis refers to the chemical process used to construct peptides in a laboratory setting without the use of biological organisms. This method involves sequentially linking amino acids to form a peptide chain through a series of chemical reactions. The most common techniques used in synthetic peptide synthesis include solid-phase peptide synthesis (SPPS) and liquid-phase peptide synthesis (LPPS).
Large-scale SPPS reactor at Bachem
In SPPS, the peptide is assembled on a solid support, typically a resin, which facilitates the automation and purification of the synthesis process. Each amino acid is added sequentially to the growing peptide chain, with cycles of coupling (adding the amino acid) and deprotection (removing protective groups such as Fmoc or Boc) occurring until the desired sequence is complete. This method allows for precise control over the peptide's sequence and composition, including the incorporation of non-natural amino acids and various modifications.
Synthetic peptide synthesis is favored for its ability to produce peptides quickly and with high purity. It is particularly effective for creating short to medium-length peptides and is widely used in research and pharmaceutical development for producing peptides used in therapeutics, diagnostics, and as research tools.
Advantages in synthetic synthesis of peptides
All of these advantages are becoming more and more important due to the increasing market demand.
Technical innovations will reduce the downsides of high material costs, scale-up and process optimization and high process mass intensity & organic solvent waste.
The current success of emerging peptide drugs for various indications is mostly owed due to solving pharmacokinetic challenges such as peptide stability, bioavailability, half-life, efficacy, renal clearance, and low immunogenicity by chemical modifications of backbone, non-proteinogenic amino acids, or side chains.
We also observe that growing molecule complexity, rising demand for speed and technological innovations drive chemical synthesis advantage and make this the preferred choice for next-generation drugs. Chemical synthesis excels in producing stable molecules, aligning with the trend towards oral administration as well. The faster production offered by chemical synthesis shortens the time to clinic and market, aligning with the industry's push for accelerated drug development. Technological innovations such as soluble-anchor based Molecular HivingTM for synthesis and MCSGP for continuous purification support the scalability of commercial production, making chemical synthesis an ever-more attractive option for pharmaceutical companies seeking to stay at the forefront of innovation.
That being said, choosing between synthetic and recombinant peptide synthesis methods still requires a balanced consideration of several factors, including the specific peptide's complexity, production volume, cost constraints, and the desired timeline for development. The future of peptide drug development will likely see innovations that address the current limitations of both recombinant and synthetic methods, ensuring that the pharmaceutical industry can meet the growing demand for peptide-based therapeutics with efficiency and agility.
Additionally, new hybrid or semi-synthetic approaches with partially recombinant, partially synthetically produced (or modified) peptide fragments which get ligated or conjugated into the full-length complex API offer an attractive and welcome expansion of the ever-growing repertoire of drug manufacturers.
«The single or combined use of chemical and biological recombination synthetic approaches allows the efficient and reliable production of synthetic peptides on large scales. These peptides can be further modified in a site-specific manner through chemical synthesis or genetic code expansion to enhance their stability and physiological activity.»
So, while chemical expertise and synthetic methods seem to have the market edge in the coming years, the final story is - as always - not yet written.
One thing can however already be concluded: These exciting developments within a fruitful innovation and competition space ultimately come to the benefit of patients.
References: