For us at Neuland quality is an obsession, as the article points out. As global pharma suppliers, we don’t put much stock into the perception that Indian pharma – or Chinese pharma (or any other particular region, for that matter) – is necessarily weak or subpar. For us, it’s a supplier issue…not a geopolitical issue.
The Cost of Outsourcing
The decision to outsource in the pharma and biopharma business is driven by one factor, and one factor only: cost. Everything else – from facilities & infrastructure, to developing & implementing a quality-driven mindset, to the collective team experience of having worked with hundreds or thousands of diverse compounds – all of those things can be acquired, given enough resources. It often simply isn’t cost-effective to do so.
So the decision to outsource is virtually always cost-driven.
But choosing who – which contract pharma provider – to turn to is driven by all of those other things that I mentioned above:
Does the provider have sufficient facilities?
Do they have the technical processes needed?
Do they have deep working knowledge of my class or specific type of compound?
What are the timelines?
Floating above all of these questions aimed at finding the supplier who is a good fit is quality:
What is the supplier’s regulatory track record?
How robust are their quality systems?
What is their quality adherence mindset?
So yes – the supplier must be able to scale a product accordingly. They must have the infrastructure and skills needed in whatever niche space the sponsor occupies. But the number one most important factor, given the highly-regulated environment we operate in? Quality.
That’s been our experience as a global provider. Since 99% of our products are exported to the U.S., Europe and Japan, we’ve always been keenly aware of quality. Our earliest FDA inspection occurred in 1997 – one of the first in India. In the article, our head of manufacturing operations – Pradeep Kumar Jain – is quoted at referring to Neuland as “a non-compromising organization” when it comes to quality. That mentality – at the core of what we do – is a key reason we’ve never once received a critical observation from any regulatory or customer audit.
Pradeep also said “production done without GMP compliance and quality in mind does not have any value to Neuland Labs or our customers” – a great reflection of our absolute insistence on quality.
With the cost pressures of today’s competitive market, active pharma ingredient (API) sales profit margins are continuously falling. As a result, pharmaceutical manufacturers find themselves under pressure to cut production costs to sustain market share and maintain position.
One particular source of production inefficiencies – current batch manufacturing and manual process control using traditional equipment – has limitations in terms of capacity and process variation. In addition to this, Deviation closure and reprocessing both increase overhead, by cutting into plant productivity and ultimately raising production costs.
A Few Techniques to Boost Your Bottom Line, Instead of Your Costs
In the process development stage of R&D, the concept of Quality by Design (QbD) can be used to understand and control processes, based on sound science and quality risk management. Design of Experiments (DOE) is very useful in optimizing & validating processes, creating accurate design space, with flexibility for operability at plant scale. The processes operating in the defined design space have more consistency and are less likely to be prone to OOS and deviations.
Plant automation can reduce human error by controlling the process parameters and ensuring consistency (e.g., temperature control, pH adjustment, rate of additions, quenching time, etc.) This also improves process safety, and semi-batch mode operation can make exothermic reactions inherently safer. Automation includes feedback control loops and special utilities, along with heating and cooling.
Automated crystallizers can offer built-in flexibility for temperature control, supersaturation, nucleation, crystal growth, and the other parameters that affect particle size distribution.
Solvent/reagent recovery and recycling during processes is a very effective and modern way to lower solvent consumption and costs, while reducingenvironmental pollution at the same time. You can also design a synthesis route (LINK TO POST ON SCOUTING) that does not generate pollutants, thereby reducing the hydraulic load sent to effluent treatment plants.
Getting More from Less
As an API producer who never competes with customer formulations, we provide continuous API manufacturing to reduce costs and meet market requirements of high throughput and process intensification. By doing so, you can get more from less.
Specifically, you can take advantage of more:
Safety in processes, with less chemicals handled per unit of time
Flexibility in production throughout product lifecycle
While also benefiting from less:
Inventory, with less money tied up in investment
Time to market
Reprocessing, resulting in less overhead and less expense for raw materials
Square footage needed for your manufacturing plant, and thus, a smaller environmental footprint
Another technique employed at Neuland is to increase productivity and yield using the most efficient equipment available in current batch processes. For example, by using a rising/falling-film evaporator or wiped film evaporator for distillation, less time is needed and quality is improved through less exposure to higher temperatures.
Putting PAT to Work for You
One final step is using PAT, or Process Analytical Techniques, during lab development and plant implementation. Using PAT tools enables a shift from Quality by Analysis to Quality by Design. This brings continuous process validation to a plant via key monitoring of critical on-line processes and operations rather than the current one-time process validation (3 to 5 batches).
PAT tools are especially useful for:
Reaction studies, using On-lineReactIR, a full-featured reaction analysis system for reaction conversion
Crystallization/Drying, via Particle Engineering studies where focused beam reflectance measurement (FBRM) and particle vision and measurement (PVM) probes are used to achieve a target particle size and shape distribution
Drying, using an NIR probe to perform an on-line moisture check or NVM (residual solvent)
At Neuland, our R&D department is establishing a dedicated research team with expertise in continuous processes, flow chemistry and particle engineering. Our research team is a QbD group supported by state-of-the-art technology and infrastructure.
With a now-established track record of successful implementations, it is clear that PAT tools and innovative automation result in cost-effective drug products while providing robust quality assurance in real time. Going forward, partnering with manufacturers who take advantage of these measures will keep your business at the forefront of pharmaceutical manufacturing.
What new techniques or technologies are you considering to increase your profit margin?
One portion of an article at PharmTech (Five Themes That Will Drive the CMO Industry) discussing opportunities for smaller CMOs recently caught my eye. It mentioned that those aforementioned opportunities for smaller service providers have been rapidly expanding, that they are a reflection of “the growing number of niche products that are getting commercial approval.”
This is certainly a very real trend in the niche spaces, and one which we are witnessing in the High Potency (HPAPI) and orphan drug spaces, to name a few.
The article (rightfully, I believe) points out the growing need for CDMO scalability – a contract provider’s ability to grow capacity in-line with client needs. But at the same time, smaller niche products are on the rise…both in terms of development as well as regulatory approvals.
Smaller CDMOs, as the article points out, tend to be more agile and responsive to client needs – and have capabilities that tend to better align with products that – at their height – still only require small batch production. Much as smaller pharma and biotech firms tend to be innovation-centric, smaller CDMOs likewise have very concentrated – and often very advanced – knowledge of specific fields.
At Neuland, we tend to play on both sides of the proverbial river. We enjoy the challenges of working at smaller scales in our research and pilot lab facilities, with an emphasis on advanced chemistry process development & optimization. Those capabilities have served us well in the orphan drug API market, a topic I wrote about earlier this year.
But we also pride ourselves for having the capabilities and expertise needed to bring early-stage compounds through to eventual commercialization at the bulk scale – effectively & economically.
The challenge for mid-sized CDMOs who handle projects that start at the bench and eventually transition to commercial scale can be integrating the different approaches such circumstances call for. On the one hand, there’s innovation and agility, while on the other hand, commercialization-focused resources & robust infrastructure come to bear.
CDMOs: In Depth Knowledge There’s no doubt your typical team at a CDMO will see far more diverse project types and process experiences than a drug manufacturer’s team would. A major strength of virtually all contract pharma partners, and (aside from cost) perhaps the biggest allure of contract research and manufacturing is the in-depth experience in one (or multiple) specific areas of scientific knowledge. In an interview on contractpharma.com (CMOs, Pharma and Outsourcing: Perception vs. Reality) Stuart Needleman mentioned that “the high level of competence that CMO scientists bring to the table is often underrated.” He goes on:
“Many CMO scientists choose the pharmaceutical discovery and development industry because they appreciate the number and variety of active programs and proposals that will regularly come their way. In most cases, this is a far larger number than they would experience if they worked at a pharma company, where the focus on individual therapeutic specialty areas can limit a wider breadth of experience.”
Small CDMOs: An Attractive Acquisition Target
As the article states, such innovative & agile small firms have become attractive fodder for the pharma acquisition machine. See a capability that clients want? Simple – acquire it. The unfortunate byproduct of this is that those capabilities can be diluted by the very act of acquisition. Agility tends to evaporate when new layers of decision-making are suddenly present. And the flame of innovation that made the small CDMO an attractive target in the first place can sputter in a strictly profit-driven and budget-centric environment.
Protecting Mindset During Company Expansion & Growth
It’s a wider, global business issue, beyond CDMOs. How does a firm stay responsive and engaged with the customer while growing to a mid-sized or larger company – either organically (as Neuland has) or through M&A?
Bottom line: it is fundamentally important to remember there are reasons small CDMOs are sought after, both as suppliers and as M&A targets. Those which grow successfully always remember that, and they embed it deep into the company mindset. Food for thought.
In today’s pharmaceutical industry, Quality by Design (QbD) has become an essential – instead of optional – tool.
In fact, the phrase, “essential instead of optional” reminds me of the Crabtree ad stating, “A switch is a switch.” (The ad emphasizes the importance of quality in a lighthearted way.) Pharma’s quality requirement has a much more serious significance, as it directly affects consumers’ health.
In a pharmaceutical context, QbD is a systematic approach to development that starts with predefined objectives. It emphasizes product & process understanding and process control, based on sound science and quality risk management.
QbD focuses on Quality planning, Quality control and Quality improvement (the J.M. Juran approach) which, further strengthened by Six Sigma – DMAIC (Define, Measure, Analyze, Improve, Control) methods, has helped advance various industries over the past 60 years. These methodologies eventually took hold in the pharma industry about 15 or 20 years ago.
At Neuland, we view QbD as a way to ensure we remain a good, sustainable business. We treat it, however, as a regulatory requirement.
Benefits of Quality by Design
When implemented properly, the various characteristics of QbD—knowledge capture, risk management and quality systems—offer a number of advantages to both sponsors and contractors…and ultimately benefit the patient.
More accurate planning allows greater supply chain reliability and predictability, which drive down the cost of goods. This can result in better product pricing and increased availability.
Faster time to market and reduced rework, resulting in lower costs and higher revenues.
Increased assurance of product quality.
Better-defined processes lead to better facilities, which can improve product reliability and reproducibility.
Potential compliance actions are reduced or eliminated.
Effective knowledge management makes it possible to work smarter and faster to make new therapies available sooner.
More opportunities for first-cycle approval.
Improved scale-up efficiency and speed.
Streamlines post-approval changes and regulatory procedures.
Allows for more focused inspections.
Offers opportunities for continual improvement.
The ability to use innovative new technologies accelerates change and enables a proactive product lifecycle marketing plan.
Builds a scientific knowledge base for all products.
Allows better interaction with industry on science issues.
QbD generates better results – not only in terms of a product’s “processability,” but also by eliminating potentially problematic unknowns when the time comes to scale up production.
Since QbD is a science-based approach, it provides a basis for optimizing and improving manufacturing without having to deal with additional regulatory filings or scrutiny. And when it comes to technology transfer, QbD-generated process understanding can smooth the transition.
Regulatory authorities feel that carrying out incremental, unsystematic improvement in unit operations in isolation ultimately has little effect on overall process performance or quality. To ensure product quality, a more holistic QbD approach should be adopted.
Throughout the process, providing explicit knowledge in a clear, concise, systematically catalogued format with the help of QbD adds a new dimension to customer service and allows companies to differentiate themselves.
Areas of Impact
It encompasses various functions such as technology transfer, control checks, deviation reduction and analytical methods development and improvement. With such a wide scope of impact, QbD renders regulatory authorities more comfortable approving the drug application.
QbD is an essential tool that fosters process understanding, and has proven to be pivotal in ensuring product quality and performance. In fact, with new guidelines in place to facilitate its use, recent NDAs at Neuland have provided numerous opportunities to demonstrate successful implementation of QbD.
Harmonizing Industry and Regulation
Full implementation of QbD is a win-win situation for pharmaceutical companies. The key issue is to understand the scientific principles of QbD and how to correctly implement it. Regulatory authorities also need to harmonize the requirements and understanding across their departments. Only with clear communication between the industry and regulatory bodies can the challenges and concerns associated with implementation be successfully resolved.
I’m not usually given to using clickbait-type headlines that scream “the sky is falling!”, but I came across a recent article which is a bit eye-opening for our domestic drug industry. Yes, India’s national security – in the form of deliverable healthcare – is suffering from the flight of API manufacturing to the Far East. And the government seems to have taken notice.
Clarivate Analytics (formerly part of Thomson Reuters) recently released a supplement to their coverage of CPhI discussing India’s dependence on China for pharmaceutical raw materials and the threat it poses to the health-care industry.
“India’s dependence on China for pharmaceutical raw materials is threatening the country’s health-care industry and pushing the government to take action.
India’s imports of active pharmaceutical ingredients (API) or bulk drugs from China reached $2.22 billion in 2015, or 5 percent up from the previous year, according to the latest statistics from the Indian Parliament.
India produces a third of the world’s medicines, mostly in the form of generic drugs, with 300 large companies and more than 10,000 medium and small-scale companies in the sector. However, less than one-fourth of them are producing APIs, while the majority – about 77 percent – make formulations.
“Many of India’s APIs and intermediates manufacturing plants have shut down,” said Ramesh Adige, a pharma expert who was formerly an executive director at Ranbaxy Laboratories Ltd., an Indian multinational pharmaceutical company. “China has emerged as the dominant player in the global API industry due to its large-scale manufacturing capabilities of APIs and intermediates. Chinese imports are cheaper and highly subsidized by the Chinese government.”
While Neuland Labs has doubled down on APIs (I’ve written numerous posts about our being a pure-play API supplier to the pharma industry), it’s a position that the pharma industry as a whole has slowly been abandoning as producers shift down the supply chain towards generics manufacturing.
Let me say – we’re not clairvoyant. We simply continue to believe in focusing on what we do best. For 30+ years we’ve been manufacturing pharma APIs via the application of complex synthetic chemistry. It wasn’t so much a recognition of a future market gap as much as a recognition that our success has always been rooted in our API capabilities and the attendant regulatory requirements necessary to produce consistently safe & effective products.
Interestingly, this issue seems to be the topic of much recent (and not-so-recent) discussion. In October, FiercePharma published an article on the topic as well. It shouldn’t come as much of a surprise, either. In 2012, a Thomson Reuters article discussed second-wave emerging markets as potential replacements for API production.
Deuterated compounds – in which drug molecule protons are replaced with deuterium to extend the drug’s half-life – continue to show promise in potentially boosting the bioavailability and safety of some drugs.
The deuterated compoundmarket has attracted many new companies looking to develop and patent deuterated versions of various existing, non-deuterated therapeutic compounds—known as the “Deuterium Switch.”
What is a Deuterated Drug? A deuterated drug is a small molecule with medicinal activity. It is made by replacing one or more of the hydrogen atoms contained in the drug molecule with deuterium – a hydrogen isotope whose nucleus contains one neutron and one proton. As deuterium and hydrogen have nearly the same physical properties, deuterium substitution is the smallest structural change that can be made to a molecule.
To Deuterate or Not to Deuterate – That’s the Regulatory Question
Developers of deuterium switch compounds must show significant clinical benefits over existing non-deuterated versions to justify why they should replace existing or less expensive therapies. However, such a switch can:
take advantage of the clinical knowledge concerning the non-deuterated version of the compound
benefit from new patent protections
result in improved therapies and patient outcomes.
Did you know that most large pharmaceutical companies today also claim deuterated versions of new molecules in their patent applications?
Benefits of Deuterated Versions of Drugs
Deuterated versions of existing drugs can benefit from improved pharmacokinetic or toxicological properties. Because of the kinetic isotope effect, which is the change in rate of a chemical reaction when one of the atoms in the reactants is substituted with one of the isotopes, drugs that contain deuterium may have significantly lower metabolism rates. As the C-D bond is ten times stronger than the C-H bond, it is much more resistant to chemical or enzymatic cleavage and the difficulty of breaking the bond can decrease the rate of metabolism. Lower metabolism rates give deuterated drugs a longer half-life, making them take much longer to be eliminated from the body. This reduced metabolism can extend a drug’s desired effects, diminish its undesirable effects, and allow less frequent dosing. The replacement may also lower toxicity by reducing toxic metabolite formation.
A major potential advantage of deuterated compounds is the possibility of faster, more efficient, less costly clinical trials, because of the extensive testing the non-deuterated versions have previously undergone. The main reasons compounds fail during clinical trials are lack of efficacy, poor pharmacokinetics or toxicity. With deuterated drugs, efficacy is not in question – allowing the research to focus on pharmacokinetics and toxicity. Deuterated versions of drugs might also be able to obtain FDA approval via a 505(b)(2) NDA filing, a faster, less expensive route.
Manufacturing Deuterium Exchanged APIs
With our expertise in deuteration technology, Neuland Labs uses a synthetic approach where deuterium-enriched material is combined with the drug to produce deuterated drugs. Another approach, called an exchange approach, uses a catalyst to produce a deuterated molecule.
The most popular process for sourcing deuterium for drugs is extracting D2O from regular water via the Girdler sulfide (also known as the Geib-Spevack) process, which uses a temperature difference and hydrogen sulfide to enrich deuterium in water by up to 20%.
Deuterated Molecules Advance in Clinical Trials
While Deuteration has been around literally for decades, I mentioned in an article last year at PharmTech (Pharma APIs: It’s Still a Small World) that most deuterium chemistry efforts are currently in the pre-formulation stage.
Those deuterated compounds that have advanced are generally performing well in clinical trials. In July, a deuterated drug reached Phase III testing for the first time, in a study to treat Huntington’sdisease. Known as deutetrabenazine, the drug was found to reduce the disease symptoms and the frequency of administration, and it is currently being considered for approval by the FDA.
The current market value of companies specializing in this technology suggests that the value of “deuterium switching” could be more than a $1 billion, and that the greatest discoveries in the field have yet to occur.
“These numbers will escalate rapidly in coming years, as the baby boom generation has begun to reach age 65 and beyond, the age range of greatest risk of Alzheimer’s. By 2050, the number of people age 65 and older with Alzheimer’s disease may nearly triple.” Alzheimer’s Association: http://www.alz.org/facts/
Globally (more so in Western Europe, less so in Sub-Saharan Africa) – the picture is similar:
Worldwide, nearly 44 million people have Alzheimer’s or a related dementia.
Only 1-in-4 people with Alzheimer’s disease have been diagnosed.
Alzheimer’s and dementia is most common in Western Europe (North America is close behind).
Alzheimer’s and other dementias are the top cause for disabilities in later life. Alzheimers.net: http://www.alzheimers.net/resources/alzheimers-statistics/
Among a broad range of health indications, Neuland Labs participates in the Alzheimer’s space as a manufacturer of Donepezil, a cholinesterase inhibitor used to treat dementia in patients with Alzheimer Disease (AD).
Donepezil works by increasing the amount of acetylcholine in the brain, which may help reduce the symptoms of dementia in patients with Alzheimer disease – such as the impairment of memory, judgment & abstract thinking, as well as changes in personality.
It should be noted that the precise mechanism of action of donepezil in patients with Alzheimer’s Disease is not fully understood, and there’s no evidence that donepezil or similar agents alters the course or progression of Alzheimer’s. Studies have found some benefit in cognition and behavior, and it is recommended as an option for treatment by both the UK National Institute for Clinical Excellence and the US FDA.
While today’s arsenal of therapeutic agents in the fight against Alzheimer’s, dementia and neurodegenerative diseases generally is stronger than ever and our understanding of AD continues to grow, there is a great deal of science left for us to learn and piece together.
I don’t mean to paint a bleak picture – plenty of groundbreaking work seems to be happening on the research side of neurodegenerative diseases. From new classes of drugs making their way through trials, to the discovery of genetic markers or other diagnostic tools to aid in detection, Every day we further our understanding of – and ability to not only manage, but also treat – Alzheimer’s and other conditions.
Unlike many API Contract Manufacturing firms, Neuland is pure-play, meaning we do not compete against our clients in the generic formulations market. Differentiating ourselves this way enables us to offer many unique benefits to our customers. Equally as important, however, it removes a major stumbling block in the relationship between the contract firm and client.
Growth in the Age of Contracting
There’s something of a rule governing most of corporate pharma these days: To Grow, Keep That at Which You’re Best, and Shed the Rest. High infrastructure costs and specific niche expertise alone make outsourcing, partnering and alliances today’s clear-cut paths to growth.
There’s a big difference, however, between outsourcing a non-core function such as manufacturing and actually ceding future market share to tomorrow’s competitor.
We’ve watched other pharma contract manufacturers forge deep into the Generics market over the years – producing their customer’s product while competing against them with an identical product formulation – and it still feels as though it pulls against the client relationship – working 180 degrees contrary to the relationship. Who wins in such a situation? And whose product is the contract firm’s priority?
The Number One Rule: Don’t Compete Against the Customer.
The most obvious benefit of a pure-play API manufacturer is that there is absolutely no element of competition with the customer. This also eliminates the possibility of any conflict of interest that could arise when working with other CMOs that are not pure-play.
I.P. – a Key Component of Strategic Pharma Outsourcing
A big advantage of pure-play API manufacturing is that we can take advantage of platform technology. We frequently use it to synthesize a variety of molecules to meet different market needs based on the platform and processes we have developed. Platform technology helps us complete our customer’s synthesis within the timeframe required.
Process Improvement Focus
Another clear benefit of being a pure-play API manufacturer is our ability to constantly improve yields and continuously work on synthetic routes to reduce the cost of APIs. As a pure-play API company, Neuland is highly-focused on continually improving our processes to get an edge on the API front. These efforts translate to providing our customers with a better value, by granting them access to the latest, most efficient, cutting-edge API technology.
An example of this is Salmeterol Xinafoate, the oral drug used to treat asthma and bronchospasms. During its manufacture, the particle size distribution is specific to the metered-dose device.
From a regulatory perspective, the regulatory risk presented by an API company can be lower than that of a forward-integrated player. This reduced risk is the result of increased control and greater uniformity across multiple sites.
Likewise, because of the nature of the work performed by a pure-play API manufacturer, even the financial risk it carries is lower because of the lower risk profile of its business. In turn, this lower risk profile ensures greater business continuity. Having a three decade-long track record in the API synthesis industry helps to prove this point.
Better Integration and Communication with the Client Finally, being pure-play allows us to work more closely with customers, fine-tune strategies, improve data-sharing and access, and customize the solutions proposed – especially where technology poses a challenge.
Learn more about Neuland Labs and how we maintain an exclusive focus on our clients’ success.
Earlier this month, we published a post on Improving Quality and Yield in Solid Phase Peptide Manufacturing. In recent years, peptides have been acknowledged for their selectivity, efficacy and safety. Combined with new synthesis technologies and advances in peptide science, peptide therapeutics have become a reality – and numerous clinical trials are ongoing.
But while peptides may be safe and effective as drugs, they have never lent themselves to straightforward commercial manufacturing – especially longer-chain, complex peptides.
In a recent peer-reviewed piece at Pharmaceutical Technology, members of the Neuland team share a newly-developed strategy to increase sample loading 7-12 fold compared to conventional Prep-HPLC techniques.
Reversed-phase high-performance liquid chromatography (RP-HPLC) is used throughout the pharma industry. Analytical RP-HPLC is used for the release and characterization of raw materials, intermediates, and APIs. Preparative RP-HPLC is used for the commercial production of peptide APIs and most other complex APIs not suited to crystallization.
Historically, there have been just two ways to increase the amount of sample that could be purified in a single Prep-RP-HPLC run: use a larger column (increase the stationary phase) or use displacement chromatography.
Advances Have Brought Commercial HPLC Closer
The technological advances in process HPLC instrumentation and the bonded silica supports have made possible commercial production of complex peptides such as Fuzeon, a 36-amino acid peptide, in hundreds of kilos quantities. Unfortunately, large-scale HPLC instruments and the associated column hardware are expensive.
More importantly, none of these improvements have addressed the loading capacity of a given column, nor have they resulted in a significant increase in the amount of purified product (output/mL of the packed column).
The New Method: SSP-Prep-RP-HPLC
In the new method described in the PharmTech article, the team used a quaternary ammonium/phosphonium salt as an additional stationary/surrogate stationary phase (SSP) – yielding to a significant increase in loadability and yield.
Chemical synthesis of very long peptides and certain sequences considered difficult is always a challenge. In this post, we’ll share a few practical tips for improving various critical aspects of solid phase peptide manufacturing during production.
During solid-phase peptide synthesis, a peptide anchored by its C-terminus to an insoluble polymer is assembled when the protected amino acids making up its primary structure are added. Aggregation of the resin-bound peptide can be problematic, and can even cause Fmoc-SPPS to fail. However, the presence of proline effectively blocks the formation of aggregates. Temporary proline mimics can be retrieved from serine (Ser) and threonine (Thr) via formation of oxazolidine, or “pseudoproline.” Smooth cleavage by trifluoroacetic acid renders the 2.2 dimethyloxazolidine ready for Fmoc-SPSS.
Racemization occurs when one enantiomer of a compound, such as an L-amino acid, converts to the other enantiomer. The compound then alternates between each form while the ratio between the positive and negative groups gradually becomes 1:1, where it becomes optically inactive. Using pseudoprolines at the C-termini of segments allows the coupling reactions to proceed free of racemization.
Pseudoproline dipeptides significantly improve the success of synthesizing long and difficult peptides. When used with peptides containing serine and threonine, pseudoproline dipeptides dramatically improve the quality and yield of crude products, and also help avoid repeat synthesis of failed sequences.
Like pseudoprolines, Dmb-amino acid derivatives also keep aggregates from forming. Dmb dipeptides are unique derivatives that improve synthesis of hydrophobic, aggregated sequences containing glycine. They work the same way as pseudoproline dipeptides, using the natural tendency of N-alkyl amino acids to disrupt the formation of the secondary structures during peptide assembly. Using Dmb dipeptides enables better and more predictable acylation and deprotection kinetics, enhances reaction rates, and improves yields, purity and solubility of crude products.
Isoacyl peptides are also notable tools for improving the efficiency of Fmoc-SPPS. Replacing Aaa-Ser or Aaa-Thr with an isoacyl dipeptide in a peptide sequence results in a marked change in the formation of the peptide chain, disrupting aggregation in a similar fashion as inserting a pseudoproline or N-Dmb/Hmb-residue. However, isoacyl dipeptides have proven to have an even greater advantage when the peptide is released from the solid phase. Unlike with pseudoproline dipeptides, the product cleaved when using isoacyl dipeptides is the depsipeptide, and not the native peptide sequence. These depsipeptide analogs of peptides prone to aggregate have been found to be more soluble and thus more easily purified than the highly structured native peptide.
All the strategies mentioned above target the fact that SPPS is limited by yields. By significantly improving yield, they effectively reduce the cost of APIs. And by improving the purity and solubility of the crude products, the entire SPPS process is made more efficient, saving valuable time and money.
Have you tried any of these strategies to improve solid phase peptide synthesis, or something else? If so, please share your experience in the comments.