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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.

Trends in Drug Supply Chain Security – API Track & Trace on the Horizon?

Supply chain security happens to be quite a broad subject, encompassing both the internals of supply chain management (e.g., having the security of multiple suppliers to manage manufacturing risk) as well as external considerations (counterfeit drugs with inferior or altered safety or efficacy profiles impacting health and safety).

Securing the Supply Chain
Pharma supply chains are complex.

And when you introduce dishonest criminal elements into an already complicated arrangement where human health and lives are at stake, they become even more challenging.

The challenges – present and emerging – facing drug supply chain security continue to grow more convoluted. This has become a hot topic in the industry for a number of reasons – ranging from patient safety and impacts on the bottom line to the increased regulatory attention focusing on what amounts to a still-growing global problem.

Supply Chain Management for Product Continuity
Internal or manufacturing-related supply chain issues are certainly very real. This year’s biggest drug shortage story so far has been EpiPen. From Five stories that speak volumes about US generics market at

“The issue at the heart of the case is the problem resides in having one manufacturer responsible for a single product that is critically important to a number of people worldwide.” In the case of EpiPen, Pfizer had difficulties manufacturing on behalf of their partner Mylan, with no secondary supplier available to pick up the slack.”

There are a number of cases in which Neuland serves as either a primary or secondary manufacturer, and we’ve even gone so far as to make sure we can manufacture a given product in multiple suites, and at different physical locations, to help ensure product continuity.

Drug Supply Chains and Patient Safety
Externally, supply chain security impacts consumers in the form of counterfeit medicines. The number of incidents is on the rise, and enforcement agencies are struggling to keep up.


“With the US and EU about to implement the next stage of their ‘track and trace’ legislation to combat illegal drugs in the pharmaceutical supply chain…every company must prepare to ensure compliance.

…With annual sales of over $1 trillion, prescription drugs lead the list of products counterfeited. The effects of these drugs can be devastating. It’s estimated that one million patients die each year through toxic or ineffective counterfeit product and that there are as many as 450,000 preventable malaria deaths annually from counterfeit pills.”

Across the Pharma Supply Chain: Complete Drug Traceability
Track and trace technologies are expected to eventually extend all the way up and down the supply c

hain, in time landing (at the molecular level) in APIs.

Another recent article (Looking to the future of a safe supply chain) predicted a rising tide for API tracking:

“We also foresee track & trace expanding its reach upstream and downstream, accommodating the tracking of the complete pharma process from an active pharmaceutical ingredient (API)/molecular level through to the actual consumption of the product…”

This topic was also referenced in a recent PharmTech article (Anticounterfeiting: In Search of the Unhackable), which discussed new innovations such as DNA tagging systems in which a strand of DNA is attached to a product which “would allow users to identify product information, manufacturing data, and chain-of-custody information on that product, and would cost less than a penny per item.”

API Tracking is Already a Reality.
In fact, such tagging has already been done. In a series of case studies demonstrating Molecular Recognition Markers for solid dosage drugs, proprietary trace markers (already approved for use by FDA CDER) were incorporated into an active pharmaceutical ingredient to allow for easy authentication.

At present, there are a number of ways to physically insert markers into solid dosage drugs. The most common – in tablet film coatings or inks – are increasingly being used for certain high-profile or high-risk drugs. But other techniques, including incorporation at parts-per-billion levels into the API itself, are becoming viable and offer the ability to implement track-and-trace capabilities earlier in the supply chain.

The Endless Loop of Anti-Counterfeiting
These are scary times, indeed. It’s a truism that technological developments (in this case, track & trace technologies) tends to play catch-up with counterfeiting or illegal practices. We’ve seen it with currencies, automotive parts, technology, software and much more. If you can imagine a product, someone has likely already figured out how to wholesale copy, forge or imitate it.

As protective measures come to market (and eventually become mandated) in the pharma industry, increasingly sophisticated counterfeiting will ultimately demand a new generation of changes to drug manufacturing processes in the future.

But there is some good news to keep in mind: we have technology and very determined scientists on our side in the fight to keep drugs safe and effective.

Non-Cytotoxic Drug Compounds & India’s GMP Schedule M

Drug product volumes have been shrinking as increasingly niche products emerge to treat various conditions. Coupled with the rise of pharmaceutical manufacturing outsourcing, this has led to a reconsideration of dedicated single-drug facilities. Many regulatory bodies worldwide have responded to this new dynamic by tightly regulating multidrug facilities. This is especially true of facilities in which cytotoxic cancer compounds are being produced – in some cases alongside non-cytotoxic compounds.

Cytotoxic Drugs vs. Non-Cytotoxic Drugs
Cytotoxic drugs – commonly referred to as chemotherapeutic agents – kill selected cells, typically malignancies and tumors. While they are sometimes used to treat other conditions, they are most frequently found in oncology therapeutics – and continue to be a rapidly-expanding pharma industry niche.

There are non-cytotoxic cancer drugs available as well. Such non-cytotoxic drugs function quite differently than their cytotoxic counterparts, and pose fewer traditional manufacturing contamination hazards.

Among the non-cytotoxic cancer drug options is targeted therapy (also referred to as molecularly-targeted therapy). Unlike traditional chemotherapy drugs which interfere with rapidly-dividing cells, targeted therapies (which can include both biological and chemical modalities – e.g., antibody-drug conjugates), typically disrupt the molecules indicated in tumor growth.

These drugs are not considered cytotoxic drugs as they do not destroy cells. In many regulatory environments they are permitted to be manufactured in a multipurpose plant – but not in India, where all drugs used for the treatment of cancer are considered cytotoxic drugs.

Manufacturing Cancer Drugs
Today, the manufacture of cytotoxic compounds is subject to a high regulatory bar, with tightly-controlled facilities possessing a robust focus on safety. Because of the cell-killing nature of the compounds, avoidance of contamination is emphasized – both of other products (in the case of a multiuse facility) or of the manufacturing infrastructure itself. India remains an outlier in this regard, employing a more stringent dedicated-facility standard than other global regulatory bodies – including the U.S. FDA.

India’s Schedule M vs. Rest of World GMP Requirements
Schedule M versus FDA GMPsWhile the World Health Organization’s (WHO) GMP guidelines emphasize the minimization of cross contamination risk, Indian GMPs (as defined under Schedule M, which lays out the requirements for facilities and manufacturing processes) call for “Separate, dedicated self‐contained facilities for penicillins or biological preparations with live microorganisms,” including cytotoxic substances. (The 4th International Summit on GMP, GCP and Quality Control published a helpful PowerPoint side-by-side comparison of India versus WHO GMPs, available here.)

While India’s GMPs incorporate those defined by WHO, they also go further in some instances – including the separate dedicated facility requirement even for non-cytotoxic cancer drugs. This came about due to the lack of any mention of such non-cytotoxic cancer compounds in Schedule M. Thus, by interpretation of Schedule M, they are relegated to the same manufacturing considerations as chemotherapeutic agents in spite of their very different mode of operation.

This restriction is beyond the scope of U.S. FDA requirements as well, which are compared in this Slideshare.

Schedule M also differs from the globally-accepted ICH Q7 Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients. The Q7 Guideline – developed in consultation with global regulatory agencies – has been adopted by the U.S. FDA, the European Union, Japan and most other regulatory authorities.

A comparison of the facility requirements in India’s Schedule M and ICH Q7 (see chart below) shows the global regulatory approach towards dedicated facilities. There is a recognition that process & quality control have evolved and tightened sufficiently over the last few decades, with the addition of “unless validated inactivation and/or cleaning procedures are established and maintained.”  Absent from ICH Q7 – and other global regulatory structures – is any mention or regulation of non-cytotoxic cancer agent manufacturing.

Why Schedule M GMPs Need Updating
There is no doubt that the extension of GMPs beyond the global standard is the mark of a strong national emphasis on quality and safety. Nonetheless, the interpretation of Schedule M bears revisiting in order to modernize India’s GMPs to account for shifting drug industry conditions. Multipurpose facilities are a way of life in the pharma industry, and even big pharma has begun the shift towards more flexible spaces as smaller, more-targeted drug volumes become increasingly common.

Equally as important, however, has been the implementation of better industry-wide practices, including improved contamination risk assessment, mitigation & management techniques – all of which rationalize a new regulatory approach.

The comparisons of practices for manufacturing non-cytotoxic oncology APIs in different regulated markets across geographies make clear that India’s regulatory stance on this is unnecessarily burdening the Indian pharma industry.

With quantum improvements in analytical instrumentation, a risk-based approach to drug manufacturing and a move towards global regulatory standardization, the need for dedicated production lines in earmarked facilities has undoubtedly diminished. Nonetheless, an incorrect interpretation of Schedule M continues to govern, impeding the global competitiveness of India’s vast pharma industry – a situation which can hopefully change in the near-term.


Neuland News: Patent Awards, New Production Blocks and Quality Management

Neuland patent awards 2018Patent Awards
Neuland recently received two IP awards – IP Gems of India 2018 and IP Excellence in India 2018.

These awards were presented to Neuland for the Company’s implementation of best practices for IP development, as well as for having made valuable contributions to Intellectual Property practices in India.

Neuland Unit III inauguration 2018Unit III Production Blocks Inaugurated
At the recently-acquired Unit III site, two manufacturing blocks (Block 1 and Block 2) were inaugurated.

Quality Risk Management
A Quality Management System (QMS) is a crucial aspect of the pharmaceutical industry. Neuland’s QMS is tasked with considering all applicable guidelines and regulations in order to remain in compliance while maintaining robust product quality and safety.

Neuland routinely holds training sessions on QMS, including the recent two-day workshop for employees from across our various manufacturing facilities. These sessions familiarize team members with major QMS topics, including APR, Change control, RCA & CAPA and Quality Risk Management. The workshop objectives?

  • Familiarize employees with the basic nuances of QMS
  • Enable employees to be better prepared to handle audits
  • Strengthen QRM across our locations



World Environment Day: Beating Plastic

There were many remarkable moments during this year’s World Cup – but the Japanese and Senegal teams and their fans really stand out for non-football-related reasons.

They gained global admiration after meticulously cleaning-up their locker rooms – and the stands! – after their respective World Cup matches.

Have common practices and habits become not-so-common these days? It should be a basic habit to dispose of trash in trashcans and not leave litter lying about. Instead, we’ve become used to admiring a group of responsible people who pick up after themselves!

It’s a timely reminder, since the theme of 2018’s World Environment Day was ‘Beat Plastic Pollution.’

The rampant use of plastic wraps, bags and bottles and their improper disposal has caused major environmental issues. Oceans, mountains, forests and cities are choking under piles of plastic. Social media is filled with images of wild animals trapped, injured and even dying due to plastic pollution.

Neuland Labs celebrates World Environment Day 2018To celebrate World Environment Day 2018 and spread awareness on Environmental Safety, several programs were arranged across Neuland’s facilities. In tune with the 2018 theme, jute bags were distributed among the employees to encourage them to choose and use sustainable products over plastic and polythene products.

Neuland’s Unit II participated in a Green Rally at Sanatnagar at TSPCB office to promote ‘green riding’ with bicycles. Teams also planted trees – an activity that always plays a role when Neuland marks World Environment Day.

Thanks to everyone at Neuland who participated – keep making a difference!

Rini Biswas, Assistant Manager of Corporate Communications at Neuland, captured this perfectly: “While the celebrations and rallies are one-time events to spread awareness, the responsibility rests on each one of us to follow a sustainable way of life to ensure a pollution free environment.”

Learn more about World Environment Day here.

Neuland Patent Spotlight: Paliperidone Palmitate & Antipsychotics

The use of anti-psychotic drugs to treat conditions such as schizophrenia and bipolar disorder is on the rise and estimated to reach $18.5 billion by 2022. It is a market driven primarily by the increased incidence of cases of mental disorders and psychosis. In a study examining the incidence of psychosis, the median global prevalence rate was estimated at 4.6 per 1000 people.

Treating Psychosis
Antipsychotics (also referred to in literature as neuroleptics) are medications targeting the management of psychosis, mainly schizophrenia and bipolar disorder. They are generally effective in providing short-term symptom relief to control psychotic behavior and reduce psychotic symptoms.

The first generation of antipsychotics (typical antipsychotics) was discovered in the 1950s. The second-generation – known as atypical antipsychotics – were more recently introduced and hold the largest share of the market, having largely replaced the earlier generation of drugs.

Paliperidone Helps Restore the Balance of Chemicals in the Brain
Among the atypical antipsychotics, Paliperidone palmitate (PLP-P) is a dopamine antagonist and 5-HT2A antagonist of the atypical antipsychotic class of medications. First approved by the FDA in 2006, it is an anti-psychotropic agent used primarily to treat schizophrenia and schizoaffective disorder.

Challenges of Manufacturing Paliperidone Palmitate
There are a number of existing methods for producing Paliperidone and Paliperidone palmitate. In most of these processes, Paliperidone is reacted with decanoyl chloride to produce Paliperidone palmitate.

With these techniques however, the 9-hydroxy group on the Paliperidone is converted to an oxo group which forms an undesirable ketone impurity.

This impurity – which may lead to undesired toxic side effects – was mentioned as a major impurity for Paliperidone in the 2007 EMEA report. It was identified as R125239 (M-12 metabolite), and considered as toxicologically qualified up to 0.62%.

Because this impurity has to be removed from the final API, most of the references in the prior-art involves the use of an extra purification step to remove this ketone impurity which not only lengthens the production time but also decreases yields.

In 2011, Neuland filed for patent protection of a new method to produce Paliperidone and Paliperidone palmitate through a novel intermediate – 3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-9-hydroxy-4H-pyri- do[1,2-a]pyrimidine-4-one palmitate ester – which is used in the synthesis process.

The patent, granted in 2015, offers an improved synthesis process for both Paliperidone and Paliperidone palmitate. The objective was to develop a process using a novel intermediate to facilitate both high purities and high yields, and avoid the formation of impurities.

In order to reduce impurity formation, Neuland’s process involves the use of palmitate ester of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-9-hydroxy-4H-pyrido[1,2-a]pyrimidine-4-one as a novel intermediate.

The process involves reacting compounds in the presence of alkali halide, base, organic solvent and a phase transfer catalyst to obtain Paliperidone palmitate.

The key advantage of Neuland’s process is the reduction of the formation of the ketone impurity which is considered to occur when introducing the palmitate ester into free Paliperidone.

Neuland’s process eliminates the need for further purification to remove the ketone impurity. This allows for Paliperidone palmitate synthesis with purities exceeding 99% – without sacrificing yield or lengthening processing time.