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A Guide to Sourcing Pharmaceutical Peptide APIs

Rise of the Peptide Era                                                                                                                                                      

Peptide synthesis has a long pharmaceutical history, stretching back to the early 1900s – and then followed by a lengthy period of dormancy. From

“Starting about a century ago (World War I), the advent of the modern drug era came with pioneering therapeutic compounds like the opiate morphine and the cyclic peptide penicillin, followed in the early 1920s by the (poly)peptide insulin. These drugs introduced a new standard in disease treatment. Although peptides thus held their place among the initial therapeutic discoveries, small molecules rapidly took preference in the drug development industry.”

Only recently have peptides gotten another look – and the pharma industry is seeing significant potential. In its most recent market report, Grandview Research estimated the peptide therapeutics market will reach nearly $50 billion. Of particular interest is what is driving the growth:

“Technological advancements in peptide manufacturing processes are one of the major factors driving the market growth during the forecast period. Manufacturers and suppliers are focusing on the adoption of novel technologies to manufacture efficient drug molecules with low time and capital investment. Improvement in purification & automation process and less generation of waste is an additional factor attributing toward market growth.”

Decreasing Barriers to Peptide Therapeutics   _________________________________________   
For peptide drugs, the list of barriers to entry have always seemed formidable:

  • high production cost & infrastructure requirements
  • rapid degradation profiles in the human body
  • corresponding lack of oral dosing delivery mechanisms
  • other pharmacodynamic limitations (short half-life, high hydrophilicity, rapid hepatic clearance, etc.)

These challenges all conspired to render the peptide class promising – but ultimately unrealizable.

It’s a far cry from the early days of pharma, when peptide-based compounds like penicillin, cyclosporine, and insulin first rose to prominence. Fast forward several decades – what exactly has changed to make peptides suddenly attractive as a therapeutic class?

Fast forward several decades – what exactly has changed to make peptides suddenly attractive as a therapeutic class?The changes have come about due to a collection of advances in chemistry, biology, genomics, dosage formulation, combined with rapid shifts in our understanding of human health and exponential improvements in technology (from computational power & informatics to spectrometry, imaging and more).

Over the last two decades, we’ve seen sufficient advances in these different but interrelated areas begin to converge, enabling not a rethinking of peptides but rather the realization of their known benefits & potential.

These developments fall into three (very) broad categories:

  • Synthetic Chemistry
    The emergence of synthetic peptide production offers significant advantages over more costly recombinant techniques, including a much wider diversity of chemical peptides and far more economical production. The use of SPPS to produce larger, more complex peptides – in tandem with hybrid techniques that combine solution phase and solid phase methods – has broadened the landscape of peptide opportunities considerably.
  • Peptide Development & Drug Delivery
    Peptide design complexity
     has also increased: developments in peptide drug conjugates, peptidomimetics and more have improved peptide degradation profiles and extended bioavailability – enabling a wider range of delivery options. Chemistry advances have also played a key role, and the chemical structure of peptides is often optimized for therapeutic use (e.g., replacing peptide bonds).Developments in the broader field of drug delivery have come into play with peptide-based therapeutics, as well. This includes alternate routes of administration being improved or developed. Peptides are lending themselves well to controlled release techniques, and exploration of non-parenteral dosing continues to expand and demonstrate viability.A number of strategies to extend bioavailability have been successfully deployed, including:

Mucosal: use of nasal sprays and sublingual use
Oral: coatings are used to protect the active substance from digestion in the stomach, or to protect the peptide against peptidases
Transdermal: patches have been successfully developed

  • Commercial Peptide Manufacturing
    Peptide manufacturing has become much more cost-efficient and capable, especially since the emergence of synthetic peptides. The push continues: peptides will continue to get larger, and cost efficiencies will continue to improve.Peptides as a rising therapeutic option are an excellent example of the slow, ponderous shift of science and technology. It was common in the early 2000s to point to a single type of science – genomics, for example, or proteomics, or informatics – and proclaim each one as the key paradigm shifter. None of them, alone, ever lived up to the hype as ‘The Science That Would Change Everything.’ But I would argue that each one has contributed to our general understanding – unlocking the next door, and opening up new opportunities.

Finding the Right Peptide Synthesis Technique__________________________________________
Peptides are a complex drug class, and have historically proven challenging from a manufacturing standpoint. They are, however, experiencing a renaissance due to improvements in peptide synthesis, the development of high-throughput approaches and various innovations to overcome some of their traditional limitations, such as stability and half-life. These advances are expected to drive the peptide drug market to over $48 billion by 2025.

Most peptides between five and sixty amino acids are produced by standard solid phase peptide synthesis (SPPS) procedures. Multiple kilos of shorter length (up to 10 amino acids) are produced by solution phase methods. For longer peptides, containing up to 120 amino acids, segment condensation and ligation techniques are employed.

Choosing the Right Synthesis Technique for Your Peptide API

The decision regarding which production technique to use is driven by three pivotal factors:

  • The size of peptide (meaning the number of amino acids)
  • The quantities needed at the current stage of development
  • The ultimate commercial launch quantities & batch sizes that will be required for manufacturing

Peptides are produced using one of three synthesis methods: liquid phase, solid phase or a hybrid approach. Each has its advantages and disadvantages.

  • Liquid Phase: 15 and Fewer Amino Acids
    Solution phase synthesis (commonly referred to as ‘liquid phase’) is regarded as the traditional approach to peptide production. Among its benefits, solution phase synthesis delivers better economies of scale. The technique is much more scalable and produces large quantities of high-quality peptides at a lower cost point than solid phase or hybrid methods. Solution phase is not well-suited to the production of larger peptides, but it is an ideal strategy for peptides containing less than 15 amino acids and when commercial requirements range from 10+ kilograms to tons.
  • Solid Phase: 25 Amino Acids & Up
    In solid phase synthesis, the peptide is constructed on resins (e.g., polystyrene, polyacrylamide, PEG).  The key advantage with solid phase is the ability to synthesize peptides which don’t lend themselves to bacterial expression using solution phase techniques.One of the major challenges facing solid phase synthesis, however, is yield – as the size of the peptide increases, yields typically decrease due to the challenge of removing closely related impurities from the product. And while some molecules don’t lend themselves to bacterial synthesis, others aren’t well-adapted to solid phase synthesis – either because of the inherent aggregation encountered during the assembly of longer peptides, or due to the chemicals used to remove them from the resin – which can damage the peptide. Production costs also tend to be substantially higher in solid phase synthesis.Conventional wisdom suggests using a solid phase approach for peptides containing greater than 25 amino acids for commercial quantities in the 1-10 kg range. Solid phase peptide synthesis utilizes an excess of protected amino acids to ensure as close to a 100% complete reaction as possible.When larger quantities are needed, this can add considerable cost to the synthesis. However, a significant benefit of solid phase synthesis is the relatively shorter cycle time when compared to liquid phase synthesis. A secondary benefit: liquid phase synthesis of peptides larger than 15 amino acids is labor intensive.
  • Hybrid Synthesis: More Than 25 Amino Acids & Larger Commercial Quantities
    The hybrid approach brings these two different methodologies together to produce peptides. For example, to construct a 40-amino acid peptide, small peptides of 5 to 8 amino acid segments would be produced using solid phase methods on resins, and then the segment condensations would occur in solution to construct the full peptide sequence.Today, a hybrid peptide synthesis strategy is generally chosen for peptides that are greater than 25 amino acids in length, and commercial requirements range from 10 to 200 kilograms. One notable success from hybrid synthesis was the pioneering work on Fuzeon, an approved 36 amino acid therapeutic for HIV-1.

Overcoming Peptide Chain Aggregation                                                                                                                      

The aggregation of peptide chains caused by intramolecular hydrogen bonds is a common challenge with longer or more complex peptides. It can result in slower and incomplete coupling reactions and incomplete deprotection of the Na-amino protecting group – meaning a modified or damaged peptide.

There are a number of steps taken to prevent aggregation during peptide synthesis, including cleavage and deprotection. The most commonly used – and mildest – method is Fmoc – the removal of the Fmoc group to expose the α-amino group. In addition to cleaving under very mild conditions, it is (typically, though not always) stable under acidic conditions as well.

Fmoc & Orthogonal Approaches to Peptide Synthesis
One of Fmoc’s greatest advantages is its ability to work well with other protecting groups (e.g., Boc) – allowing for an orthogonal approach – a common strategy in organic peptide synthesis.

Common Fmoc Methods for Disrupting Peptide Aggregation
Advances in peptide synthesis methods and ready availability of reagents that disrupt intramolecular hydrogen bonds have made complex syntheses much more practical. There are three Fmoc strategies for disrupting aggregation. The decision to use each one is directly dependent on the type of building block being used.

Rising to the Challenge: Emerging Peptide Tech                                                   ____________                        
Peptide purification techniques that can increase the resolution between related substances and the API are critical for establishing identity, purity & assay – and for increasing the preparative output. The ultimate goal: high-quality, affordable peptide APIs.

Evaporation – the most commonly used crystallization method for small peptides – is scalable, but isn’t an effective technique for producing or analyzing complex peptides. Emerging technologies, however, are playing in a key role in overcoming these hurdles. Hghlighted below are two such innovations driving improvements in purity and yield.

Molecular HivingTM
Developed by Neuland Labs’ collaboration partner Jitsubo Co. (Yokohama, Japan), Molecular Hiving is a manufacturing scale technique which offers tremendous cost advantages over traditional methods, whether LPPS or SPPS (Solid Phase Peptide Synthesis).

The technique uses TAG, hydrophobic benzyl alcohol or benzyl amine derivatives at C-terminus – instead of resins in solid phase synthesis (SPPS). The reactions of coupling to form peptides and deprotection of N-Fmoc or Boc in slightly hydrophilic solvent are performed in homogeneous solution (typical of LPPS).

Precipitation and isolation of a desired tagged-peptide is easily performed by adding a hydrophilic solvent to the reaction mixture.

By using its patent-protected achiral hydrophobic tags, peptide solubility can be controlled. A synthesis begins with the attachment of a patented hydrophobic tag to the C-terminal amino acid.

Peptide chemistry reactions are then performed in a hydrophobic solvent. When the reaction is complete, the tagged peptides can be precipitated and filtered.

The process effectively removes excess reagents present in the reaction mixture, providing high yields of high purity peptides.

In science labs, reversed phase high performance liquid chromatography (RP-HPLC) is used to analyze, characterize, separate, purify, and isolate small organic molecules, natural products, and biologically active molecules such as polypeptides, proteins and nucleotides.

In pharma, analytical RP-HPLC is employed specifically to release and characterize raw materials, intermediates and active pharmaceutical ingredients (APIs). Likewise, preparative RP-HPLC is used to commercially produce peptide APIs, along with most other complex APIs that cannot be crystallized.

The new method developed by Neuland uses C-18/C-8 derivatized silica, coated with a hydrophobic quaternary ammonium salt or quaternary phosphonium salt. It increases 7- to 12-fold the sample loading of the crude mixture of organic compounds including synthetic crude peptides. What causes such dramatic results is the additional surrogate stationary phase characteristic of the C-18/C-8 bound quaternary salt.

Secure Your Peptide API Supply Chain.
Supply chains have become mission-critical for the pharma industry, and peptide API manufacturing is no exception. Helping clients improve the security of their supply chains means maintaining the security of our own capabilities. At Neuland, we leverage ‘insulating facilities,’ a redundancy which provides customers with seamless, rapid supply transition in the event of a disruption. Contact us today to learn more about our capabilities, tools and techniques for peptide drug development & commercialization.

Deuterated Drugs Reach Two-Year Anniversary

We’ve reached the two year anniversary of the first FDA approval of a deuterated molecule (April 2017, Teva’s Astedo – a deuterated version of tetrabenazine for the treatment of Huntington’s disease). It’s interesting to have witnessed the emergence of this unique space.

Deuteration of drugs came to prominence in the 1970s, but it took 40+ years for the first such drug to reach the market.

Teva’s Astedo (Deutetrabenazine) is similar to other deuterated products in that it possesses a longer half-life compared to non-deuterated versions of the same (often already-approved) drug. Generally, deuteration alters the metabolic, toxicological and pharmacokinetic properties of a drug – though it has been reported that most drugs would not derive any benefit from deuteration.

What is a Deuterated Drug?
From an earlier post we wrote on deuterated molecules: A deuterated drug is made by replacing a drug molecule’s carbon-hydrogen bond with a carbon-deuterium bond. As deuterium and hydrogen have nearly the same physical properties, deuterium substitution is the smallest structural change that can be made to a molecule.

Why Deuteration Matters
There are a number of well-known benefits to deuteration, including:

Lower Dosing
Deuterated drugs break down at slower rates than non-deuterated versions, resulting in a longer duration in the body. This translates into lower or less frequent doses.

Reduced Toxicity
Fewer doses resulting from the longer half-life, in turn, can reduce the toxicity of the drug in the body. A 2019 article in Annals of Pharmacotherapy found that deuteration “may also redirect metabolic pathways in directions that reduce toxicities.”

Increased Stability
Fewer drug interactions can occur due to the stability of deuterated compounds in the presence of other 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, lengthening the timeline for elimination 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. (Read more: API Manufacturing of Deuterated Molecules.) 

Patent Uncertainty – but Regulatory Certainty
The last decade has witnessed the rise of patents claiming deuterated versions of non-deuterated drugs.  The intellectual property aspects of deuteration, however, remain a question mark.

Patent law has been the most problematic venue for deuterated molecules, primarily with concerns over the ‘obviousness’ of the invention. While there has yet to be any resolution to this uncertainty, it hasn’t stopped pharma companies – including Big Pharma – from adding deuterated versions of a prospective compound to their patent claims.

From Taylor & Francis online:

“The total value of transactions involving deuterated drugs is close to $5 billion. While the importance of §103 ‘obviousness’ rejections remains in patent applications under current prosecution, IPR of issued patents is developing and will affect likely affect §103 interpretations in this area. However, patents are still issuing with later priority dates, and further litigation will likely occur.” touched on the use of deuterated molecule patents as a defensive action in a 2017 article (Drug Developers Look to Deuterated Drugs as Risk Managed Opportunity):

“Patents are expected to play a major role in this segment, largely because the majority of deuterated drugs under development are approved APIs in undeuterated form. This dynamic has given rise to a significant level of defensive IP activity, in which companies patent deuterated APIs largely on speculation that the drug will prove to be efficacious and safe at some point in the future.”

On another front, deuteration in the pharma industry has received some much-needed clarity. With the regulatory status of deuterated compounds presumably settled by the FDA (FDA Determines that Deuterated Compounds are NCEs and Different Orphan Drugs Versus Non-deuterated Versions), there has been a further upswing in interest in the space.

Deuterated Drugs: Progress & Promise
The opportunities may stretch well beyond those listed in the chart below. A January 2019 article in the Journal of Medicinal Chemistry stated that deuteration:

“might provide an opportunity when facing problems in terms of metabolism-mediated toxicity, drug interactions, and low bioactivation. The use of deuterium is even broader, offering the opportunity to lower the degree of epimerization, reduce the dose of co-administered boosters, and discover compounds where deuterium is the basis for the mechanism of action.”

So what is happening right now in the field with deuterated candidates? Here’s a chart with indications and clinical status, of products ranging from Phase 1 all the way up to Phase 3.

Contact Neuland Labs today to discuss your deuterated compound needs.

Inside Sugammadex: Overcoming Impurities in Commercial API Manufacturing

The first in the class of drugs known as selective relaxant binding agents (SRBA), Sugammadex sodium is used to reverse anesthesia. Via 1:1 binding of rocuronium or vecuronium, it rapidly reverses any depth of neuromuscular block while avoiding cholinergic adverse effects. The generic ingredient in Merck’s Bridion®, Sugammadex reverses the effects of neuromuscular-blocking drugs that freeze vocal cords and muscles during surgery – allowing patients to be taken off breathing machines and go back to breathing on their own sooner.The first in the class of drugs known as selective relaxant binding agents (SRBA), Sugammadex sodium is used to reverse anesthesia.

Process Challenges Overcome by Neuland
Neuland has developed a robust, scalable, operationally safe process which consistently produces product as per desired yield and quality at higher volumes. The synthetic process consists of 3 steps:

  • Stage 1: Prior art process involves the use of PPh3/I2 as a reagent for iodination which results in the formation of triphenylphosphine oxide as a by-product in a stoichiometric amount. The removal of the same is cumbersome. Neuland’s process involves the use of PCl5/DMF for chlorination.
  • Stage 2: Prior art process involves the use of NaH/DMF for reaction with 3-Mercaptopropionic acid which is pyrophoric and hazardous. Neuland’s process involves the use of 30% NaOMe solution in DMF in this stage.
  • Stage 3: Prior art process involves the use of dialysis purification which is neither feasible nor economical at an industrial scale. Neuland’s process involves preparative HPLC for purification and isolation of the final product by lyophilization.

In tech Sugammadex-Na (Stage 2), impurities at RRT 0.89 and 0.96 are very difficult to remove and attributed to Stage 1 intermediate quality. This was accomplished with purification by crystallization and achieves 85% purity as per Stage 2 specifications.

The preparative HPLC method is sensitive to many variables, including input material solubility, pH, and column performance—all of which were largely overcome with appropriate checkpoints in the process.

A process was also established to improve yield for the failed fractions unable to load into the preparative HPLC column directly.

Neuland is the first generic player to have a granted process patent for the preparation of Sugammadex Sodium in India (IN 290882/Expiry: Aug 25, 2030), USA (US 9120876/Expiry: Jan 15, 2032) and Europe  (EP 2609120B1/Expiry: Aug 23, 2031).

Neuland’s API quality meets the regulatory requirements regarding any SMUI to NMT 0.089%, based on dosage value.

Early launch opportunity:

  • A formulator can launch a product with Neuland’s Sugammadex API after November 2020 in the key markets India, Turkey, Canada and Brazil.
  • US Market: A formulator can launch a product with Neuland’s Sugammadex API by filing ANDA with Para-IV.
  • EU Market: A formulator can launch a product with Neuland’s Sugammadex API after July 24, 2023 when the product patent expires.

To discuss opportunities and find out more about launching a product with Neuland’s Sugammadex, contact Neuland Labs today.

The Unblockbuster – Speeding Cures with Specialty Drugs

For years, industry soothsayers have suggested the imminent demise of blockbuster drugs was upon us (here’s one from 2009 – Goodbye blockbuster medicines; hello new pharmaceutical business models).

But two short years ago, Humira reaped a windfall $16 billion in revenues for maker AbbVie, and was expected to garner $20+ billion in 2018. In fact, Humira is expected to well exceed the $150 billion in lifetime sales achieved by Pfizer’s Lipitor. Other top blockbuster drugs have posted only slightly less-impressive totals.

So are blockbusters really dead?

No, of course not. Here’s a chart from 2014 (right), and nothing has radically changed in the last few years.

But that doesn’t mean “Find the Next Blockbuster” is still the prevailing business model of your average drug company. In fact, business models have meaningfully shifted over the past few decades – especially in the last ten years.

Blockbusters Didn’t Go Away, They Just Got Siblings.
Today’s business model looks less monotone and more like a smorgasbord: M&A, licensing, blockbusters, generics, orphan, niche or expedited-review drugs, and more. In some cases it extends beyond pharma and biopharma, to include devices, diagnostics, healthcare, or other niches.

The trend away from a blockbuster-only model (fewer, bigger $1+ billion drugs) has been a long time coming.

Many companies – even Big Pharma – now use a diversified approach, combining fewer blockbuster-targeted drugs and a collection of niche therapeutics aimed at specialized or rare disease markets. In a SlideShare on LinkedIn, K. Gurjar pointed out the position taken by Glaxo’s former CEO on the blockbuster-only model: It’s a “business model where you are guaranteed to lose your entire book of business every 10-12 years.”

‘Rumors of the Demise of Blockbuster Drugs Have Been Greatly Exaggerated.’
While companies have adopted a multi-faceted approach to the pharma business, they have by no means abandoned the blockbuster drug entirely. In fact, 2019 is expected bring a diverse range of up and coming blockbusters, and even some top drugs that have already fallen off the patent cliff continue to perform well.

But with that being said, it is the niche (specialty) drugs that are attracting significant attention. Returns on investment are notably better, with the blockbuster model returning an estimated 5% ROI and only 1 in 6 drugs delivering returns above their cost of capital.

Specialized drugs, with targeted segments, offer some advantages along the path to market & commercialization. Orphan drug status, expedited reviews combined with smaller, less-competitive and higher-likelihood-of-return markets offer multiple opportunities to spread out and diminish risk. Such strategies are obvious winners in pharma forecasting & projections circles, where lower risk profiles can equate to better accuracy.

2018: The Year of Orphan and Special Drugs
2018 proved a banner year for niche drug approvals. In FDA Marks Record Year for New Drug Approvals (at PharmaTech), the subtitle says it all: “Orphan and cancer drugs continue to lead, but treatments for many common diseases were also approved in 2018.”

Faster Drug Approvals

Last year, about half of new drug approvals benefited from expedited FDA review, whether orphan drug status, Accelerated or Priority Review, Fast Track, or Breakthrough Therapy. Fully one-third of the approvals were designated as orphan drugs for rare diseases.

A banner year for shorter approval processes, however, does not spell doom and gloom for blockbusters. Rather, it highlights the shift towards a balanced drug commercialization approach in which drug companies aim a portion of resources at those big-dollar runaway success drugs while maintaining a substantive portfolio of candidates that benefit from less expensive, faster processes.

Cynthia Challener mentioned in the PharmTech article, “These results suggest that both pharma companies and FDA remain committed to leveraging the shorter approval pathways made possible in the 2012 Food and Drug Administration Safety Innovations Act.”

2018’s list of FDA approvals may have also been indicative of the progression of precision medicine. Clinical populations are being further segmented to deliver more targeted therapeutic responses to highly-specific disease states. Some of these are orphan indications for rare drugs – something with which Neuland is quite familiar.

And the Future Trend is…
At its start, 2019 looks to flip 2018’s script with a focus on common – rather than rare – medical conditions. From PharmTech:

Most of the drugs on FDA’s approval docket through early 2019 include treatments for many common conditions, including heart disease, immune deficiency, diabetes, and influenza.”

In spite of this data point, it’s a safe bet to assume we’ll be seeing more niche drugs – with enough blockbusters thrown in for good measure to keep us all guessing about their eminent demise.

Pharma Tech Transfer Gets Collaborative

Drug manufacturing technology transfer is one of the most complicated and demanding processes in the drug company-contract development organization relationship. There is one overriding deliverable that must go right – the scaled-up successful production of a drug. However, there are countless things that can go wrong during the course of the scale-up.

Drug manufacturing technology transfer is one of the most complicated and demanding processes in the drug company-contract development organization relationship. There is one overriding deliverable that must go right – the scaled-up successful production of a drug. Pharmaceutical API transfers to the commercial scale can frequently stretch a year or more, often due to the involvement of regulatory agencies.

In a noteworthy piece at PharmTech (Tech Transfer: Tearing Down the Wall), Agnes Shanley discusses the growing integration of the technology transfer process with other pharma company resources and assets.

Where a few decades ago, research department staffers might speak glibly of throwing a process “over the wall” from R&D to scale-up and manufacturing, today most organizations realize how wasteful that approach has been and are approaching tech transfer in a much more systematic and collaborative way. Cross-functional teams are usually the rule, with representatives from each major operational group (e.g., quality, business, research, and operations) at the sponsor group taking an active role in moving projects forward.

Some of this evolution has come about by virtue of changes or developments in the broader pharma industry. Technology has played a role in bringing historically removed teams closer together. Regulatory demands as well as an increasingly data-driven environment have also pushed pharma tech transfer towards close coordination with other groups or teams.

Inter-Departmental & Cross-Company Collaboration
This is true for us at Neuland, as well. Tech transfer and scale-up are a key part of what we do. Our tech transfer team coordinates closely with scientific research teams, scale-up engineers, quality, process development, EHS and more.

In a blog post on Quality By Design, we discussed how Neuland leverages QbD to bring together a collaborative and inclusive team comprised of both chemists & engineers to ensure a successful API scale-up. QbD is a valuable tool when evaluating “what-if” drug scenarios.

In another earlier post on the subject (Leveraging QbD for API Scale-Up) we explained how QbD enables robust technology development & transfer to manufacturing:

“With cause & effect analysis of Critical Process Parameters (CPP) on Critical Quality Attributes (CQA), QbD also aids in robust technology development & transfer at manufacturing plants. In order for QbD to aid in scale-up, an appropriate control strategy needs to be in place to ensure a focus on critical points.”

While transfer complications can (and sometimes do) emerge with a drug’s API synthesis technique at larger scales, they are easier to address when multidisciplinary teams approach the challenge with their collective knowledge and skillsets. 

Smart pharma tech transfer teams tasked with the challenge of designing a product’s course through scale-up need maximum access to information and expertise. Informed Decision-Making
The era of siloing operations, hoarding data & know-how, and proverbial Chinese walls between teams is long-past over. Technology has provided us with a new creed: efficient collaboration.

Smart pharma tech transfer teams tasked with the challenge of designing a product’s course through scale-up need maximum access to information and expertise. This allows them to make the most accurate decisions possible to ensure a candidate or drug’s success.

Tech Transfer – Start Early
Many pharma professionals would argue that the tech transfer phase is the perfect time to address scale-up issues, but this can negatively impact the opportunity to streamline scale up and tech transfer operations.

Ideally, scale-up issues would be analyzed and addressed during process development. After all, what’s the feasibility of a process that would require 8 million liters of acetone and 113 weeks to yield 1/100th of a 50 milligram dose of product?

Invention at the bench does not necessarily translate to practicable commercial-scale manufacturing.  Thinking about these issues early during process development helps address product viability proactively, rather than reactively.

As a contract API manufacturer, we see a surprising number of companies who still view tech transfer as “where you shake out all the process issues.”

The biggest challenge with this mindset? It usually means inadequate or partial knowledge transfer.

This commonly leads to project delays as additional work must be performed to fill in any knowledge gaps. In some cases, we are able to fill those gaps with our own collective experience working across a range of APIs and therapeutic classes.

Find & Fix Formulation Issues Before Scale-Up
Joseph Szczesiul of UPM Pharma discussed the need to get it right early and avoid reformulation during tech transfer at PharmTech:

“The best foundation for tech transfer success is complete formulation and process development. You cannot correct formulation deficiencies during tech transfer, and process optimization can only provide limited improvement. An inadequate enteric coating, for example, or a wet granulation with insufficient binder, can only be improved incrementally by process changes. The big fix comes from formulation change, which needs to be done early in the development process.”

This is why it is so important that there should be constant, ongoing discussion as well as information review & sharing with clients. As our knowledge of their product and process increases, we must effectively communicate this information to the client.

The Bottom Line
Effective technology transfer requires comprehensive information about the process in question…and cross-functional teams are the answer. Bringing the collective wisdom and capabilities of multiple departments together to solve tech transfer challenges should be a no-brainer.

TIDES TV: The Past, Present & Future of Peptides

Dr. Mike Anwer – Neuland’s President of Peptide Synthesis – recently sat down with Andy Busrt of TIDES TV to discuss the peptide drug market.

Peptides – From Insulin to Fuzeon

It’s worth remembering that some of our earliest drugs – think insulin – were peptide-based. After that, there was a prolonged silence from a seemingly capable class with loads of potential.

A number of significant advances occurred in those years, including:

  • The synthesis of the first-ever human hormone in 1954 (Oxytocin).
  • The introduction of a racemization suppressing agent to improve coupling reactions.
  • The introduction of the drug Fuzeon – a 36 amino acid peptide – for the treatment of HIV.

We’ve mentioned Fuzeon before, and it’s importance to the commercialization of peptide drugs should not be underestimated. The efforts by Roche and Trimeris to bring Fuzeon to market shifted the peptide industry, leading to the establishment of low-cost suppliers for the key starting materials.

From Chemical & Engineering News: “That…makes Fuzeon one of a few peptide drugs to have been made in near-ton annual quantities. And beyond sheer volume…it proved large-scale production of a long peptide is possible. Fuzeon production broke ground in terms of equipment and process design.”

Peptide Challenges: Supply Chains Must Be Built & Strengthened

Dr. Anwer highlighted some of the key challenges with peptides – namely, cost and accessibility.

The industry needs more consistent quality, and better supplier reliability. The performance in the supply chain must improve to keep pace with developments in chemistry.

Bringing Down Peptide Costs and Increasing Quality

Cost, in spite of the advances made since the introduction of Fuzeon, remains a significant barrier for peptide-based therapeutics. Consider that generally, purification costs account for more than 20% of a Peptide API’s costs.

When it comes to producing hundreds of kilograms of 20 to 30 AA-peptides, improvements in purification yield and output are urgently needed to meet these challenges.

On the quality front, a concerted API quality improvement campaign should start with:

  • High chirally-pure amino acid derivatives (key starting materials should possess >99.5% chiral purity).
  • Greater involvement from process development chemists.
  • Better purification media & instruments.

From a manufacturing perspective, moving away from traditional Bac- chemistry would mark a major paradigm shift. Most manufacturers would then be discussing a 100-kilogram peptide order as if it was a small molecule API.

All told, there are a range of improvements that will drive the peptide market, from improvements with key starting materials to improvements in the coupling and purifications stages, and better post-purification as well.

Technology & Capabilities as a Peptide API Differentiator

As mentioned earlier, peptide purification accounts for more than 20% of the cost of a Peptide API. This has always been a key hurdle to overcome with peptides, and differentiation in the market among manufacturers will likely focus on a combination of expertise and novel techniques.

Dr. Anwer points out that Neuland is a leader in peptide technologies and capabilities. While the Company’s considerable experience with peptides is comprehensive, there are a number of particular contributions Neuland has made to the field of peptide manufacturing. Two of these are the wide use of precipitation to improve starting purities, and the use of SSP-RP-HPLC to dramatically increase final yields.

Upfront Precipitation

While many peptide manufacturers use precipitation, Neuland’s use of it as a primary step provides an effective way of ‘polishing up’ the starting materials – removing impurities that limit the loading capacity of the column in subsequent purification steps.

Better Purification

Neuland has developed and patented a preparative HPLC Technology that has 5X to 20X more purification output than the standard reversed phase preparative HPLC. This technique utilizes hydrophobic quaternary ammonium salts as additional/surrogate stationary phases. (You can read more about Neuland’s patented peptide chromatography purification technique in this post).

Starting Materials Source

Neuland has also built a range of difficult- or costly-to-produce study resources and starting materials. These include derivatized lyine, DD, hybrid DDE derivatives and pseudoprolines. Neuland is considered a global root source for about 34 pseudoprolines.

On the manufacturing side, Neuland is a leader in liquid phase peptide synthesis. Among our projects, we have produced 35 kgs. of a decapeptide by liquid phase (using a 24-step synthesis process, and are currently producing 100 kgs. per year of a 15-amico acid peptide (a 40-step liquid phase synthesis process). We also have several 30-amino acid projects using standard solid phase as well as hybrid technologies.

From Acute to Chronic: Strong Outlook for Peptides

In the early days, peptides were primarily used for acute indications, such as the use of oxytocin during childbirth. With chronic indications such as diabetes and oncology, peptides are needed in larger quantities. This need is expected to continue growing due to the wide range of therapeutic indications for which peptides have potential. The reason? The natural amino acids used to construct peptides. These amino acids do not have the toxicological or genetic impacts that can arise from synthetic molecules.

Dr. Anwer’s prediction?
The peptide industry will evolve to meet the challenges discussed above. In 10-15 years as many as 50% of all drugs could be peptide-based.

Stay tuned!

Inside Neuland Technology: Bosentan Monohydrate

Pulmonary arterial hypertension (PAH) is a rare disease affecting 1-2 people per million in the U.S. and Europe.

The orphan drug Bosentan, a dual endothelin receptor antagonist, is used in the management of PAH.

4-Tert-butyl-n-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-pyrimidine-4-yl]-benzenesulfamide, monohydrate – better known as Bosentan – functions by blocking actions of endothelin molecules that promote the narrowing of blood vessels, which leads to high blood pressure.

Bosentan was introduced in 2001, the first of a new class of PAH drugs – endothelin receptor antagonists (ERAs). Today it is available in both tablet and suspension forms.

What is Pulmonary Arterial Hypertension (PAH)?
The World Health Organization (WHO) classifies PAH among the 5 groups of pulmonary hypertension – a condition in which the arteries become narrower, thickened or are blocked entirely.

According to the NIH: in the United States, about 1,000 new cases of pulmonary arterial hypertension are diagnosed each year. This disorder is twice as common in females as in males.

The orphan indication PAH “occurs when the very small arteries throughout the lungs narrow in diameter, which increases the resistance to blood flow through the lungs. Over time, the increased blood pressure can damage the heart. 

Reducing Impurities During Bosentan Monohydrate Manufacturing
Using traditional techniques to synthesize the Bosentan sodium has the drawback of yielding about 2% potential impurities, typically hydroxy-, styrene- and dimer impurities. For example, one common synthesis technique resulted in the formation of undesirable ethylene glycol bisulfonamide, which is a dimer impurity.

This leads to increased efforts geared towards controlling impurity formation, and generally requires repeated purification steps.

The downside, of course, is that yields suffer and manufacturing costs rise.

Bosentan Manufacturing Today
A team at Neuland studied this challenge, and developed an improved process to produce a crystalline form of Bosentan. The process yields less than about 0.2% of the three above-mentioned impurities, and consists of fewer processing steps.

Neuland began manufacturing the Bosentan API in 2011. The Company has been a granted patent (which expires in 2033) for a novel crystalline form of Bosentan sodium, the key intermediate of Bosentan.

Bosentan is an example of how a contemporary approach to API process development can create efficiencies. In some cases, this can result in:

  • a less expensive process
  • a faster process
  • a process which generates less effluent.

Adopting new approaches to older compounds can also extend the lifecycle of a drug class, or create other new opportunities.

Learn more about Bosentan opportunities in North America and Asia/Pacific.

Inside Propofol: Tackling the Challenges of Lipophilicity

Neuland began manufacturing Propofol in 2012, and filed a USDMF in 2013. Some drugs and APIs are more challenging to produce than others – and Propofol is an excellent example.

If the name Propofol rings a bell, it’s likely because the drug has spent time in the news over the last decade or so. This included one widely-reported case of off-label usage – Michael Jackson’s overdose – as well as product recalls, legal stumbles and a shuttered manufacturing plant in China.

Anesthetic Shortages
Propofol (often marketed as Diprivan) is an injectable anesthetic typically used in general anesthesia during surgery. (The active pharmaceutical ingredient is also available from Neuland.)

Propofol was approved for use in the United States in 1989. Today, it resides on the World Health Organization’s List of Essential Medicines.

In the early 2010s – as sterile injectable drug shortages plagued the U.S. market – Propofol was high on the FDA’s drug shortages list. [It was reported that 80% of drug shortages involved sterile injectables, many of which are critical anesthesia or chemotherapy agents used in hospitals and surgical centers.]

How bad were the problems? In 2010, CBS reported:

“Propofol’s string of bad luck is almost outlandish: Two companies…have stopped supplying it after a series of recalls, contaminations, and a $500 million jury verdict, in addition to the bad press from the [Michael] Jackson death. When the FDA warned doctors Propofol was in short supply, the volcano in Iceland interrupted new product from being flown in.”

It wasn’t until three years later that reported (2013): “As Propofol comes off its shortages list, the FDA says manufacturing problems still cause the majority of supply issues though legislation has helped to alleviate this.”

It’s a difficult-to-formulate and difficult-to-manufacture compound, as sustaining a stable aqueous solution of propofol can be challenging.

While supply issues may have stabilized over the past few years, the drug’s production remains complicated.

Propofol (often marketed as Diprivan) is an injectable anesthetic typically used in general anesthesia during surgery. The active pharmaceutical ingredient in Propofol is available from Neuland.Propofol Manufacturing Challenges
There are a number of production challenges with Propofol, all stemming from its complicated formulation and expensive, difficult and lengthy manufacturing process – with minimal tolerance for deviation.

What are some of the specific commercial manufacturing complications which must be overcome?

  • Propofol has very high lipophilicity. Propofol’s highly lipophilic nature is due to isopropyl substituents on the ortho position of an aromatic ring. To overcome this, emulsions are created. But there are drawbacks, including emulsion instability. The compound’s extreme lipophilicity necessitates dispersion in soybean macro emulsions in order to produce a white, opaque formulation.
  • Propofol is also air-sensitive, and exposure to oxygen during manufacturing & packing must be avoided. For this reason, it is typically packed using aluminium containers in a nitrogen atmosphere and then stored at 2 – 8 degrees C.

Manufacturers must take strict measures as the type of oil or liquid used for emulsions and any exposure to an oxygen environment form oxidative impurities and encourage growth of microorganisms.

A New Generation of Propofol?
The need for such measures in the processing and manufacture of Propofol has driven exploration of alternate (and easier) formulations.  For example, it has been hypothesized that Propofol could be associated with biocompatible surfactants to form transparent, colourless, thermodynamically stable, low viscosity, oil-in-water micro-emulsions with droplets having a 10- to 50-nm diameter instead of macro emulsions.

Neuland and Propofol
In the meantime, bulk Propofol manufacture continues with tried-and-true – and very exacting – techniques. Neuland purifies the product using fractional distillation to get consistently high quality & yield.

Neuland began manufacturing Propofol in 2012, and filed a USDMF in 2013. We were also granted a Certificate of Suitability (CEP) demonstrating compliance with the relevant monograph of the European Pharmacopoeia by the EDQM within 9 months of filing (today’s industry average is 18 months).

Neuland’s proven Propofol manufacturing capabilities rely on our expertise with complex chemistry, our dedication to rigid quality assurance and our decades of experience synthesizing molecules at the commercial scale.

Learn more about Propofol, or discuss available marketing & distribution opportunities around the world. Contact Neuland Labs today.

Drug API & Peptide Trends: 2019

With the global population continuing to both increase and age, pharma industry growth is likely to continue. While facing pricing hurdles in well-established mature markets, the emerging drug markets (China, in particular) seem poised to continue flourishing.

What impact, if any, will this have upstream in the drug supply chain, notably among API and peptide producers?

Factors which bear watching in 2019 are:

Focus on Optimizing Bulk Efficiencies
Over the last few years, cost pressures have struck up and down the supply chain, and contract pharma firms haven’t emerged unscathed. Process optimization is no longer something that is done to solve a particular production process, such as finding a new synthesis route to overcome process viability issues.

Today, optimization is an absolute must – to control production costs, to reduce or eliminate EHS issues, to decrease lead time, to improve the safety or efficacy profile, to adapt to new or updated regulatory guidance and more.

This reinforces the need to use ‘bulk-think’ at the earliest possible process development stages. It’s a mindset that encompasses many different aspects and strategies. The use of Design of Experiment and QbD play a huge role. But is also necessitates a change in approach, where the overarching goal of a commercially-viable, safe and efficacious, effluent-minimizing manufacturing process is always front-and-center – even at the earliest stages.

China’s Role in API Manufacturing
Scandal after scandal has cast a long shadow over quality. This chain of events has been disastrous for China’s massive API manufacturing industry. While increased regulatory oversight may help alleviate concerns in the long-term, growth will likely be hampered by increasing trade tensions and uncertainties between the U.S. and China. (We discussed this at length in our last post, Pharma API Supply Chains: Mitigating Risk.)

Other reservations haven’t helped. China’s crackdown on pollution has sent some global companies scrambling to find alternate material sources or bring manufacturing in-house.  While the net effect of improved enforcement will undoubtedly be positive both with polluters and pharma suppliers – better quality, fewer ‘bad’ suppliers – it leads to short-term ambiguity and risk.

Year of the Peptides?
Peptide-based therapeutics have been a promised rising force over the last ten years or so, following decades of inactivity. Their potential hasn’t been overstated. Once unlocked, peptide drugs could deliver fewer side effects and better efficacy at lower dosages, though technical challenges with drug delivery still remain.

As with all new (or, in this case, re-emerging) drug classes, ascendancy often happens in fits and starts. An article last year at Drug Discovery World captured this concept in their headline: Oral Peptide Therapeutics – A Holy Grail or Quixotic Quest?

The answer is likely somewhere in between ‘holy grail’ and ‘quixotic quest.’ The authors note: “Though peptide therapeutics offer numerous advantages, and the growth of such drugs is strong, there remains a significant gulf between ‘market actual’ and ‘market potential’. This is largely attributable to challenges with the route and method of delivery of peptide drugs.”

2017 – the last full year for which data is available – set a 20-year record for overall drug approvals (46), of which six were peptide-based. The future for peptides remains very bright, and we are closely watching drug delivery developments.

Supply Chain Security
Supply chain security issues remain big-picture for everyone in the drug industry. We have recently seen the migration of track and trace up the supply chain – from packaging to tagging active drug substances with molecular biomarkers. The explosion of counterfeit drugs poses a big challenge, and regulatory agencies worldwide are focusing on solutions.

Geopolitical & Trade Concerns
Another macro concern, which relates to both China and trade issues generally, has been the global emergence of nationalist sentiment. Coupled with trade conflicts and a collective sense of insecurity facing the established – and very globalized – system of business that has emerged over the last 60-odd years, we’re seeing more requests to ensure multiple redundant suppliers or facilities are available to drug companies seeking to mitigate risk.

Pharma API Supply Chains: Mitigating Risk

The risks to pharmaceutical supply chains grow in parallel with the industry itself. As drug markets have become increasingly complex and global in nature, so – too – have drug ingredient supply chains.

Today’s top threats to the drug supply chain remain regulatory & quality issues and capacity limitations. But these threats themselves are subject to a variety of both internal and external forces and risk factors.

From drug quality issues to natural disasters, an almost endless parade of complications can arise. Coupled with a shift in 2018 towards more aggressive trade actions and policies, pharmaceutical manufacturers face an almost unprecedented array of supply chain challenges that can be tough to quantify, project and mitigate.

China Stumbles Upwards
The prominence and sheer scale of the Chinese drug market is undeniable. It is among the drug industry’s overall top growth drivers – China possesses a burgeoning middle class, and coupled with a globally aging population, offers significant market opportunities. As the market for drugs has emerged in China, so have Chinese suppliers and manufacturers – and the last few years have not been kind.

A large number of recalls and facility closures (some driven by falsified vaccine data) provided a real-world test for China’s emerging regulatory authority (CFDA). It has also challenged understaffed U.S., European and other global regulatory bodies.

As the result of various regulatory issues and the rapidly growing scale of the Chinese drug industry, the FDA and others ramped up local staffing to address the volume. China’s CFDA has been significantly up-staffed as well – though the jury is still out on whether the proper resources will be allocated and whether a decentralized GMP inspection regime is sustainable.

These regulatory actions have been part of a much larger trend. In 2015, data suggests there were 7,000-9,000 drug and API manufacturers in China. More recent estimates point to about 4,500. From CPhI: “The number of [API] suppliers has decreased through a combination of mergers, acquisitions, and closures.”

While the overall impact of increased Chinese regulatory actions is expected to be positive and lead to improving confidence, the short term impact on the industry has been rising prices and growing attention to supply chain risk.

As the regulatory ramp-up occurred, China was also continuing efforts towards its Blue Sky initiatives, aiming to tackle the increasingly dire pollution plaguing the country.

Their measures have met with undoubted success: overall PM2.5 levels in Beijing had fallen by 40% from their peak in 2012-2013. But polluting industries may be migrating south, where smog levels are rising.

But there has also been a steep cost increase across multiple, affected industries. New tax laws that came into effect in 2018 are targeting polluters – including API producers.

Some API producers near to the major cities like Beijing and Shanghai have been asked either to slow down or close operations. Many other upstream organizations who met global regulatory standards for drug production nonetheless closed down operations due to the increased environmental protection efforts.

The Impact of China’s API Industry Challenges
The last few years have delivered a strong blow to the Chinese API industry, but impacts were felt well beyond China. Global drug companies had to work quickly to identify alternate supply sources, leading to product shortages and manufacturing delays. In addition, partially as a result of the environmental and regulatory issues and partially due to increased automation, prices have been rising.

Supply Chain Anxiety in the C-Suite
As a lesson in the risks of single-sourcing, the China situation served its function. And it’s one reason why drug company execs consistently identify supplier security and risk management as a key challenge. It’s a situation that in 2018 was compounded by geopolitical events and potentially far-reaching trade disagreements – injecting even more uncertainty into global supply chain planning.

Thriving on Predictability
Maintaining supply integrity demands appropriate risk management. Global drug firms want their suppliers to have appropriate strategies and redundant capabilities in place to preventatively manage risk. The more predictable a system – the less risk to be managed.

Managing supply chains both upwards and downwards is always a safe move for manufacturers. Securing your own supply chains allows you to deliver your clients greater certainty and security upstream.

Mitigating Supply Chain Risk With ‘Insulating Facilities’
It’s also how we function at Neuland. Helping clients improve the security of their supply chains means maintaining the security of our own capabilities. One of the ways in which we’ve increased security is via ‘insulating facilities.’ Our recently-acquired Unit III, for example, is an FDA inspected site for the production and supply of intermediates which can be used to insulate our other manufacturing facilities (Units I and II) from supply-chain disruption.

Thriving on Predictability
Maintaining supply integrity demands appropriate risk management. At Neuland, we’ve addressed this internally by identifying certain high-impact intermediates which can be backward integrated to manufacture in Unit III. This can help alleviate congestion in Units I and II, while offering the structural scope and set up for future expansion. And as independently-inspected facilities, this redundancy provides customers with seamless, rapid transition of supply in the event of a disruption.