Last year’s valsartan contamination and recall brought some surprising chemical synthesis issues to light in the pharma industry. While the reactions used in generic valsartan production are known to be a source of certain impurities, they were below current disregard limits and didn’t raise any red flags. It was the impurities that no one thought to look for, however, which led to the recall.
Valsartan is an angiotensin receptor blocker, or ARB, used to treat high blood pressure & heart failure. Neuland Labs does not manufacture valsartan, but the chemical synthesis risk management takeaways from this series of events apply uniformly across the API industry.
When Novartis’ patent for valsartan expired in 2011 in Europe and in September 2012 in the U.S., manufacturers of generic active pharmaceutical ingredients (API) raced to develop their own synthesis processes. A market that in 2010 was worth six billion USD was about to open its doors.
Judging from the patents filed around that time, Novartis/Ciba-Geigys original method for the tetrazole-forming step relied on the use of tributyltin azide. The yield of this step was 65%.
Generic Valsartan – Better Yields, But Hidden Toxicity?
With valsartan, higher synthesis yields were critical in order to achieve costs low enough to capture the business of pharma companies.
Various methods for forming 5-substituted tetrazole cycles on nitrile groups with sodium azide had been around for some time – relying on the use of metal catalysts, strong Lewis acids or tertiary amines.
In September 2010 Zhejiang Huahai patented a sodium azide-based synthesis method for valsartan, resulting in much improved yields approaching 90%. At the time the inventors boasted: “The method has the advantages that the operation is simple, the yield is high, the product purity is high, and the industrial production is easy.”
But sodium azide, it turned out, was a dangerous substance whose toxicity compares to that of potassium cyanide. It was fatal if swallowed, inhaled or put in contact with the skin. Since the new synthesis method required bringing a stoichiometric excess of sodium azide to the reaction, an unreacted residue of this highly toxic substance would remain in the product.
To deal with the toxicity of sodium azide, Zhejiang Huahai’s valsartan process chemists opted to add nitrous acid to the production broth as soon as an in-process control confirmed the complete formation of the tetrazole cycle. They did so in the form of sodium nitrite – which in the acidic environment of the broth turned into nitrous acid. Nitrous acid was a known decontaminating agent of sodium azide. It caused the degradation of sodium azide to nitrogen gas, nitric oxide and sodium hydroxide. The toxicity issue was thus resolved.
NDMA: Toxicity Tragedy
Zhejiang Huahai patented this production method in 2014, but their valsartan process had been based on the use of sodium azide as far back as 2012. Tragically, Zhejiang Huahai’s chemists failed to realize that while eliminating the toxicity due to sodium azide, their process generated another toxic substance: N-nitrosodimethylamine (NDMA) – a probable carcinogen in humans.
The solvent of the tetrazole-forming step was dimethylformamide, whose industrial production process starts from dimethylamine. It is now suspected that the residue of dimethylamine in the solvent reacted with nitrous acid to generate NDMA.
The presence of this contaminant remained undetected until early June 2018, when the manufacturer was reviewing and optimizing its processes. It is important to underline that the levels of NDMA eventually identified in valsartan were well below 0.05% – the disregard limit of the European and American pharmacopoeias for the related substances of valsartan.
According to the European Medicines Agency (EMA), NDMA was found in Zhejiang Huahai’s valsartan, on average at 66.5 ppm, and at most at 120 ppm – enough to represent an unacceptable health hazard, but not enough to be distinguished from analytical noise during routine quality control of valsartan.
Besides, whereas HPLC was used for control of the related substances of valsartan, gas chromatography would be the preferred method for separating NDMA. In 2017 FDA investigators had reported occasional issues with the tests of impurities during inspections of Zhejiang Huahai, but those issues were not critical and concerned chromatography peaks above the disregard limit.
Since it was below the normal reporting level of impurities, the presence of NDMA had been missed for years, not due to any fault of the company’s quality control. Rather, it was missed as a consequence of the faulty assessment of the safety of the synthesis process.
The presence of the NDMA contamination implied that the company’s European pharmacopoeia (CEP) certificate of suitability for valsartan was wrong. The European Directorate for the Quality of Medicines (EDQM) thus suspended the validity of the certificate as soon as the contamination became known.
The EDQM assessors of valsartan’s CEP application dossier had failed to realize the risk, as had Zhejiang Huahai, the U.S. FDA and everyone else.
Sodium Nitrate – a Missed Red Flag
The risk of formation of carcinogenic nitrosamines from nitrites and secondary amines in acidic conditions has long been known to the food industry. It was not rocket science – yet it came as a surprise to the pharmaceutical industry.
The use of sodium nitrite in the valsartan processes of Zhejiang Huahai and other manufacturers should have been a red flag prompting an evaluation of any presence of secondary amines, but it did not. From this perspective, it would be a mistake to see Zhejiang Huahai as an exceptionally careless actor.
In fact, quite the contrary seems to be the case.
Better Synthesis Risk Management
This company actually managed the risk of genotoxic and mutagenic impurities better than the average manufacturer. For instance, in one of their products – dabigatran etexilate mesylate – Zhejiang Huahai had specified a tight ppm acceptance limit for control of the potential presence of ethyl mesylate.
Ethyl mesylate is a genotoxic substance known for having caused a carcinogenic contamination in Nelfinavir at a Swiss plant in 2007. Such careful controls are not commonly seen at mesylate substance manufacturing plants.
Zhejiang Huahai’s discovery of the presence of NDMA in valsartan in June 2018 was – of course – overdue, but anyone familiar with the API industry will recognize that it was beyond what the average generic API company would likely do.
How often do we see an elective ICH M7 compliance program at any API plant? Rather than any exceptional sin on the part of the manufacturer, the valsartan contamination event might reveal that the pharmaceutical industry – focused as it is on the quality of pharmaceutical ingredients – has not been paying enough attention to the safety of chemical synthesis processes.
As soon as the valsartan contamination became known, the manufacturer and regulatory authorities rushed to test NDMA in other company products. They were satisfied to detect no NDMA in those products.
Irbesartan, which is another tetrazole molecule, was one of those products. Like valsartan, Zhejiang Huahai synthesized it according to the sodium azide method. Unlike valsartan, though, no dimethylformamide was used, but triethylamine was – which implied the natural presence of a residue of diethylamine from the manufacturing process of triethylamine by alkylation of ammonia with ethanol.
Looking for the Right Impurities
Because sodium nitrite was used in this process, the potential contaminant that needed to be tested in irbesartan was not N-nitrosodimethylamine (NDMA), but Nnitrosodiethylamine (NDEA). Everyone was looking for the wrong impurity. Just like the valsartan process, the chemical synthesis process of irbesartan had not been carefully studied. The scope of investigation was extended to other valsartan manufacturers, as well.
On 16 July 2018, the European Medicines Agency wrote to a number of manufacturers of the substance to inquire about their production methods for a re-evaluation of risk of generation of NDMA. Obviously, the investigation will also need to be extended to candesartan cilexetil, irbesartan, losartan and olmesartanmedoxomil, as these substances contain 5-substituted tetrazole cycles that are formed through the same method based on sodium azide.
It seems we will have to look deeper and wider than just NDMA in valsartan.
A Proper Response to Drug Contamination
We can be confident the valsartan contamination incident will be corrected although some patients will suffer serious consequences. Zhejiang Huahai reacted to their discovery responsibly. They halted production, sealed the stocks at the warehouse, and promptly notified the authorities and customers. The synthesis process will undoubtedly be modified, and NDMA will be routinely evaluated in valsartan.
This event will eventually be brought under control. But we would do well to understand that the contamination of valsartan remained undetected for years because the industry’s approach to the quality control of pharmaceutical ingredients tends to focus on the generally-harmless related substances of synthesis.
The Future of API Quality Management
The troubling question is: How many NDMA, NDEA, ethyl mesilate and other highly toxic, low concentration, impurities might lie hidden in the hundreds of pharmaceutical ingredients made by thousands of manufacturers around the world?
Something needs to change in our quality management of pharmaceutical ingredients, not only to prevent similar contaminants in the future, but also to become aware of the ones which may be there – right now – in our medicines.
This article was first published in Neuland’s internal newsletter, Neuworld, by Ashok Gawate – Neuland’s General Manager of Developmental Quality Assurance & Regulatory Affairs.
Peptide process development projects have increased in the last few years. Judging by our blog readership and social interactions, interest in peptide drugs is continuing to grow by leaps and bounds.
We’ve seen questions focused on whether a given peptide can even be produced give way to questions focused on whether a peptide can be produced at X volume, for Y cost and at Z purity.
Peptides are a unique class of drugs nestled between small molecules and proteins. Between 1920 (the introduction of the world’s first peptide drug – insulin) and 2017, more than 60 peptides have been approved by the FDA.
Peptides are attractive as a drug class due to their high specificity and low toxicity, but certain properties have historically limited its utility (e.g., parenteral route of administration, proteolytic instability, etc.). These are among the limitations of peptides that are currently being overcome, and have been the focus on increased research and industry attention over the last decade or so.
We’ve written on a number of peptide topics over the years, and much of our focus has been on the various techniques used to synthesize the peptide API – liquid phase, solid or hybrid.
History of Peptide Synthesis
Peptide synthesis technique selection is extremely important. The very first liquid phase synthesis of a peptide hormone, Oxytocin, was reported in 1954 – an elegant synthesis for which Vincent du Vigneaud received the Nobel Prize.
In 1963, Robert Bruce Merrifield reported synthesis of a tetrapeptide (4 amino acids) using solid phase synthesis. While solid phase synthesis is convenient to perform, liquid phase synthesis is preferred for peptides which:
Most of our peptide projects extend well beyond synthesis technique selection and development to encompass other key areas of peptide drug commercialization.
Scale-up, confirmatory batch production, process optimization and analytical methods development are all milestones on the path a peptide therapeutic takes through clinical trials to market. It is the collective advances in these related disciplines – better chromatographic resolutions, or our greater knowledgebase for methods creation and validation, for example – which have contributed to the resurgence of pharma peptides.
16 Amino Acids. 100 Kilograms. 98% Purity!
Our previous liquid phase synthesis of a decapeptide (10 amino acids) at 35 Kg scale involved 24 steps. At the time, we considered this a very significant peptide manufacturing milestone for Neuland.
Then one of our U.S.-based customers asked us to develop a liquid phase synthesis route for a cyclic sixteen amino acid peptide API which possessed multiple disulfide bonds.
They also wanted the peptide scalable to 100+ kilograms per year.
For this particular API, Neuland developed a liquid phase synthesis strategy using four protected segments, including:
Overall, the final process involved 40 isolated stages. Each stage required evaluation of optimal reaction conditions. For each of the 40 steps, reaction parameters – including temperature, reactant molar ratios, and pH – were optimized.
Specific analytical methods were also developed, and critical process parameters and critical quality attributes were established for each stage.
To demonstrate scalability, Neuland prepared all the segments in several hundred grams quantities (with purity exceeding 95%).
Process consistency was established by conducting three lab verification batches for each of the stages. The yield for the verification batch of the lyophilized peptide API (post-preparative HPLC) was ~30% and the final API purity was 98+%, per the customer’s specification.
The Peptide Class is in Session
While this was just a single project at Neuland, it was an example of a successful – and quite complex – liquid phase synthesis scaled to commercial volumes.
From analytical and process instrumentation to novel peptide assembly methods, much has happened to pave the way for the peptide API industry to routinely discuss projects at 100+ kg/yr scales…at 98+% purities…across 40 manufacturing steps.
We’ve reached a juncture where complex peptide manufacturing techniques and instrumentation are starting to bend the cost- and scale curves, just as the science of peptides seems to be coming to fruition. This is building a more compelling revenue case for peptide therapeutics – something that has generally been out of reach.
The peptide class, it seems, is in session.
Alzheimer’s Disease (AD) is a heartbreaking and tragic condition affecting millions of families worldwide. This month, we highlight how health and pharma intersect.
Gender & Alzheimer’s Disease
Gender is a key risk factor for Alzheimer’s Disease…much more so for women than men.
From the Journal of Alzheimer’s Disease:
“The incidence of the disease is higher in women than in men, and this cannot simply be attributed to the higher longevity of women versus men. Thus, there must be a specific pathogenic mechanism to explain the higher incidence of AD cases in women. In this regard, it is notable that mitochondria from young females are protected against amyloid-beta toxicity, generate less reactive oxygen species, and release less apoptogenic signals than those from males. However, all this advantage is lost in mitochondria from old females.”
How much more likely are women than men to suffer from AD? Cognitive Vitality, a program of the Alzheimer’s Drug Discovery Foundation, reported last summer that “more than 5.5 million Americans are living with Alzheimer’s disease, of whom two-thirds are women.”
Treating Alzheimer’s Disease
Worldwide, 50 million people suffer from Alzheimer’s and other forms of dementia. While there are currently no drugs which can cure Alzheimer’s outright, common drug interventions for AD can – in some patients – temporarily alleviate the symptoms or slow their progression.
Such drugs include cholinesterase inhibitors such as the Donepezil, which is approved to treat all stages of Alzheimer’s. Other cholinesterase inhibitors (Rivastigmine and Galantamine) are approved to treat mild to moderate AD.
The Alzheimer’s Association discusses another drug, Memantine (Namenda) – as well as a combination of memantine and Donepezil (Namzaric) as treatments which are approved by the FDA for moderate to severe Alzheimer’s.
There are also a number of drugs in various stages of development worldwide, including selective beta secretase inhibitors, immunotherapies, inhibitors targeting the accumulation of tau, anti-inflammatory combinatorials and more.
Neuland is a manufacturer of Donepezil – the generic API of Aricept (we produce both Donepezil base and Donepezil hydrochloride). Donepzeil was first approved in 1996, and is a reversible acetylcholinesterase inhibitor. As an enzyme blocker, controlled studies have shown modest benefits in cognition or behavior. While it does not cure Alzheimer’s disease, it may temporarily improve memory, awareness, and the ability to function.
Ending Alzheimer’s – #ENDALZ
While drugs such as Donepezil can provide modest temporary benefit, the focus this month is on ending Alzheimer’s entirely. Essential to this are ongoing efforts to build awareness – awareness of Alzheimer’s disease itself, its progression & stages and its signs & symptoms.
Preventing Alzheimer’s Disease: What You Need to Know
While scientists continue to look for a cure to Alzheimer’s, or at least a way to stop it’s progression more permanently, there are steps we can take to ensure our brains remain as healthy as possible. Check out these tips from Harvard Health on keeping your brain healthy.
Want More Alzheimer’s Resources?
The NIH’s National Institute on Aging is a good resource for general information on Alzheimer’s Disease, and CenterWatch has updated lists of dementia-related research and clinical trials. DDNews’ yearly neuroscience report is also worthwhile – here’s the April 2019 report.
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 sciencedirect.com:
“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:
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?
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:
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
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:
Peptides are produced using one of three synthesis methods: liquid phase, solid phase or a hybrid approach. Each has its advantages and disadvantages.
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.
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.
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:
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.
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.”
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.
“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.”
Drugdiscoverytoday.com 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.
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.
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:
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:
To discuss opportunities and find out more about launching a product with Neuland’s Sugammadex, contact Neuland Labs today.
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.”
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:
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.
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.
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.
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.
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:
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:
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.
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.
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.
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.
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:
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.