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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.’

#BeatPlasticPollution
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.


Big Pharma Keeps Getting Bigger…by Shrinking?

An article at Pharma Manufacturing (Shrinking Big Pharma) pointed to the recent movement among Big Pharma towards smaller production floors.

It comes as no surprise.

With the rise of target-based drug discovery, the era of the blockbuster drug is fading –  being replaced by a growing need for smaller, more nimble production units that can better address today’s need for lower-volume (and increasingly niche) therapeutics.

In 2014, the New York Times reported: “Seventy percent of new drugs approved by the F.D.A. last year were so-called specialty drugs used by no more than 1 percent of the population.”

The years between the launch of the first blockbuster (SmithKline Beecham’s Tagamet, in 1993) and the present have seen many new drugs reach blockbuster status.

The wider adoption of generics is also having an impact on the long-term ‘blockbuster’ potential of drugs. Drugs are losing sales to generics faster than ever today.

In spite of the rise of targeted therapies & generics, many drugs are still projected to become blockbusters. According to DRG: “about 200 launches are expected during 2017-2019, of which approximately 14% are forecast to become blockbusters.”

Shifting Drug Manufacturing Approaches
With that being said, pharma firms are recognizing there’s a shift towards precision medicine – and they are modifying their approach to drug manufacturing accordingly.

There are a number of reasons why companies are rethinking their manufacturing facilities and shrinking their production footprints. Here are several of the top reasons behind the shift towards smaller production blocks:

  1. Cleanrooms: Cost per Square Foot
    Larger production blocks tend to be…well… This means more cleaning, which translates to additional manpower, equipment, consumables and time. In aseptic processing environments, the larger the space – the more surfaces there are to maintain…and the higher the costs.
  2. Decreasing Demand for High Volume Drugs
    As the industry focus shifts towards smaller-volume personalized drugs, Big Pharma needs to up their flexibility – allowing them to adapt to both blockbusters and niche therapies.
  3. Smaller, More Flexible Manufacturing
    Cutting edge production suites get more production out of less space, with the flexibility to repurpose the space as needed. As the article notes, companies are “looking for and successfully finding ways to make manufacturing more compact, flexible and mobile.”
  4. Equipment Diversification
    This is an issue which touches many industries, beyond the scope of pharma or biopharma manufacturing. At some point, firms begin to see the value of multiple smaller systems rather than one single massive production line. It permits scalability, and ultimately decreases system complexity and downtime.

These considerations have been S.O.P. among many contract manufacturers for quite a while. Since firms such as Neuland tend to work with a broad array of products – from orphan up to blockbuster-sized drugs – offering a diverse range of flexible production blocks has proven critical to our success and growth.


Case Studies from Neuland’s Process Engineering Lab

In our PE Lab, a team of 27 highly specialized engineers integrates the key attributes of QbD process understanding, process control, and continuous improvement with advanced equipment, Design of Experiments Software, and Design Space methodology.

The objective? To optimize process design, develop inherently safer process using the principle of QbD by DOE based on process safety studies for cost competitive and safer commercial process to improve productivity.

At Neuland, our clients have ready access to our fully operational, dedicated Process Engineering Lab (PE Lab). The lab features state-of-the-art instruments, systems and innovative devices to support operations and safety studies using a QbD approach.

Equipment includes a stirred, controlled HEL reaction calorimeter that measures the rate of heat release during reactions along with gas release if any during the reaction. Automated parallel HEL reactors enable multiple experiments to be carried out at temperatures ranging from -60 to 225oC. The lab’s new Thermal Screening Unit (TSU) indicates the thermal stability of chemicals and safe processing temperatures. Ideal for risk analysis, the TSU uses only 0.5-5 g of a sample.

Solving Customer Process Safety & Particle Engineering Issues
In the year since the lab opened, our team has solved numerous process safety and particle engineering challenges for our customers. Highlighted below are just a handful of the exciting projects we’ve taken on.

Anti-Convulsant O6 Process Safety Project
To ensure process safety for the anti-convulsant O6, we optimized the process parameters and demonstrated the process on a commercial scale 350 Kg batch, using PE lab infrastructure data.

We followed this success by filing a patent. The table below details the steps (lick to enlarge):

Neuland Labs Anti-Convulsant O6 Process Safety Project

Anti-Tuberculosis Drug Process Safety Project
Another process safety case involved an anti-tuberculosis pipeline drug, a Custom Manufacturing Solution project at Neuland. The customer explained how they were dumping all the reagents and then heating to reaction temperature, as this was scale-dependent.

After thorough evaluation using the TSU, we determined the reaction initiation temperature. The reagent causing exotherm was added at 2°C above the reaction initiation temperature. The batch was produced at plant scale without any problems, then converted from batch mode to semi-batch mode. Automation controlled additions based on both the process temperature and gas release rate.

Predicting the Stability of a Micronized API Project
To meet the physicochemical properties required for an API and optimize particle size distribution (PSD) and bulk density requirements of a final drug formulation, engineers and scientists in the PE Lab leveraged particle engineering techniques and particle size reduction and drying technologies.

They also conducted experiments designed to assess the stability of a micronized API at lab scale. The goal was to be able to predict and – if needed – implement corrective actions to avoid stability-related failure when using a multi-mill, micronizer or fluidized bed dryer to produce commercial batches.

Particle Engineering & Anti-Thrombotic Drugs Project
Our team has also conducted particle engineering experiments using Micronization to meet customer PSD requirements for products such as Indacaterol maleate (less than 5 microns PSD achieved) and Ticagrelor (less than 10 microns PSD achieved). Ticagrelor is used to prevent thrombotic events such as heart attack in people with acute coronary syndrome or myocardial infarction.

Particle Size and Levetiracetam Project
Data generated on experiments with the compound Levetiracetam were used to optimize process conditions to meet the PSD requirement. Having achieved PSD, the different products were dispatched on a Kg scale. Stability testing of the micronized material under real-time/accelerated conditions assessed the impact of the micronization protocol on impurity profiling. Data generated on experiments with the compound Levetiracetam were used to optimize process conditions to meet the PSD requirements.

Concept of Membrane Technology
Reverse osmosis technique is used for concentrating the reaction mass. Dia filtration for        removal of salts for cost competitive, scalable process. The concept was used in resolving for API based Amino Acid synthesis and for addressing yield & quality concerns for one of the anesthesia products.

Flow Chemistry & CSTR in seriesNeuland Labs Anti-Convulsant O6 Process Safety Project Developed in-house capabilities in flow chemistry and generated proof of concept for handling of hazardous reagents (Strecker reaction NaCN, LDA reaction) at intensified conditions with reaction progressing with less than a minute. Improved Oxidation Reaction Yield and Quality. Executed at plant with desired Yield & Quality., obtained Yield ~65-70% compared to ~30% earlier campaign outsourced. Oxidation reaction done in CSTR’s at lab and obtained acceptable yield and quality. The technology of CSTR’s in series is filed for patentability.

The Problem-Solving PE Lab at Neuland
Data and insights gathered in the PE Lab help our engineers and scientists develop robust processes at lab-scale for new products, ensure inherently safer processes, and understand the complexities of scale-up to enable right-at-first-time technology transfer, minimizing failures at plant scale. Knowledge and data are essential. Well-designed experiments performed in batch mode can test for hazardous reactions and suboptimal unit operations, informing how we define process parameters and controls to implement at scale.

 

Questions about process engineering? Contact us to see how we can help.


Ringing Hyderabad: Neuland’s Home in Genome Valley

With the recent acquisition of Unit III, Neuland’s footprint around Hyderabad continues to grow.By peculiar235 - MindSpace campus https://en.wikipedia.org/wiki/Hyderabad#/media/File:Hyderabad_Outer_Ring_Road_and_its_radial_roads.png

Hyderabad, for those not familiar with India’s fourth most populous city, is a hive of finance, information technology and pharma. It also spreads across 650 km2 (250 square miles) – making it one of the largest metropolitan areas in India, as well.

It’s a city that has successfully evolved from a traditional manufacturing city into two of its more recent namesakes – ‘Cyberabad’ and ‘Genome Valley’ among them.

Pharma in Genome Valley
The Pharma industry is widely distributed around Hyderabad, but generally spreads north from the city outwards. Major regional players include Dr. Reddy’s, Divis Labs, Aurobindo, Novartis, Mylan and others.  (Medindia data found more than 360 major and small pharmaceutical companies reside in Hyderabad and nearby the city in 2015 – and that figure has only risen.)

There are a number of key attractors for pharma in the region – from financial to infrastructure and more. But one of the crucial differentiators is its ready-to-go workforce.

Hyderabad and Pharma Talent
The talent pool is often cited as Hyderabad’s biggest attraction to the pharma industry. The abundance of pharmacy colleges and the availability of students and graduates have led to Hyderabad becoming a top pharma industry hub in India.

How abundant are educational institutions?

The city and its surrounding environs host more than a dozen Colleges of Pharmacy, Schools of Pharmacy, and Pharmacy colleges alone. Hyderabad also offers an array of Centers of Excellence across numerous disciplines, and many other educational and research institutions.

One further benefit of the depth of talent in the region should be pointed out: it spurns pharma and biopharma innovation and the potential for new startups. And some – or perhaps many – will choose to remain in the region, further stimulating the industry’s growth.

Neuland and Hyderabad
Neuland Labs has facilities spread around the general Hyderabad region.

Our Corporate headquarters are located closer to the center of the city – between Hitech city and downtown.

Neuland’s Unit I is situated about 40km from Hyderabad in Bonthapally on an 11-acre campus. The facility offers 7 production blocks for small volume high-value production. Vessels range from 20-3,000 liters.

Unit 1, which has been inspected by the FDA, EDQM and PMD, also hosts kilo labs and other supporting departments, including Quality Assurance, Quality Control and Regulatory Affairs.

Typical products manufactured in Unit 1 include: Antiasthmatics, Cardiovasculars, Antifungal, Anticonvulsants, Antiemetic, Central Nervous System (CNS), Fluoroquinolones, Corticosteroids and others.

Situated alongside Unit I are our R&D Center, Pilot Plant, Kilo Lab and Process Engineering/QbD Labs…all of which focus on bringing new complex molecules with efficient manufacturing processes to market.

Neuland Labs Unit II (and soon III)

The FDA, EDQM, TGA cGMP and WHO GMP approved Unit II, about 45 kilometers from Hyderabad airport, is a high-volume facility with 6 production blocks and total reactor volumes of 310 KL. Typical product lines include Fluoroquinlones, Anti-Ulcerants, and Prostaglandins.

Neuland Labs’ recently-acquired Unit III is expected to come on line in 2019 with an additional 197KL of capacity and additional room to grow in the future. The 12-acre facility will offer 5 advanced intermediate & API production blocks, analytical method development & quality control labs, and a pilot plant. (Read our earlier post welcoming Unit III.)


Emerging Peptide Technology Spotlight: Molecular Hiving

Molecular HivingEarlier this year, Neuland began working with a technology called Molecular HivingTM along with Jitsubo Co. (Read the March 2018 press release here).  It’s a patented technique to manufacture peptides with innovative TAG-assisted liquid phase peptide synthesis (LPPS), and delivers high-quality & low-cost peptide APIswith short lead times.

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

Molecular HivingTM – Combining the Benefits LPPS & SPPS
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.

TAG-assisted peptidesMolecular Hiving: How it Works
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.

Peptide APIs: Benefits of Molecular HivingTM

This peptide synthesis technology achieves the key advantages offered by both of the standard peptide manufacturing techniques – solid phase peptide synthesis (SPPS) and liquid phase peptide synthesis (LPPS). Molecular HivingTM offers a potential range of benefits, including:

  • Highly efficient synthesis without the use of excess raw materials.
  • High-purity peptides can be manufactured due to process monitoring.
  • Minimized loss during downstream processing due to high-purities obtained upstream.
  • Combination of LPPS benefits (quality, cost efficiency & process control) with SPPS benefits (short lead times and long sequence capabilities).
  • High reactivity during synthesis, allowing for easy isolation of the targeted peptide during work-up.
  • Fast process, allowing for shorter lead times. Reaction times, for example, are very short, and operation steps can be completed in 1-2 hours.

Peptide drugs in developmentGrowing Opportunities for Peptide APIs.
New technologies such as Molecular HivingTM will play an important role in helping to deliver on the promise of the peptide class of therapeutics. Anything that can move to needle on cost – a key challenge with therapeutic peptide APIs – should be considered a very exciting technology. The promise of high-quality-while-affordable peptides is a key reason why the Jitsubo technology is potentially a key manufacturing differentiator.

From Neuland’s standpoint, the potential to bring together Jitsubo’s Molecular HivingTM technology with Neuland’s specialized purification technology and peptide capabilities is very exciting. We see this research and development collaboration in the field of peptides as a way to complement our strength in peptide manufacturing (Solid, Solution and Hybrid phase) & our own proprietary purification technology with an innovative – and commercially cost-effective – technology.

Want to learn more about complex peptide manufacturing? Contact Neuland today.


Generic Drugs: Despite Dominance, Consumer Perception Issues Linger

Generics: U.S. Drug Industry Dominance
The last time you filled a prescription, was it a generic or a brand name drug?

An astonishing 89% of all drug prescriptions in the U.S. are filled with generics.

Of particular interest as far as cost savings are concerned: that 89% only represented 27% of drug expenditures. At pharmamanufacturing.com (Generic But Mighty), Karen Langhauser writes:

Generic and biosimilar drugs have rightfully earned their place as part of the solution. In the U.S., generics account for 89 percent of prescriptions dispensed but only 26 percent of total drug costs. Generics have saved the U.S. healthcare system $1.67 trillion in the last decade, generating $253 billion in savings in 2016 alone.

Generic drugs are not a small opportunity, and they already do their share of heavy lifting in the U.S. healthcare market. But generics do face a number of hurdles – some of which Langhauser discusses in the pharmamanufacturing.com article. In no particular order, the top four include:

  1. Consumer Misperceptions
    “Safety not proven” despite bioequivalence, “different side effects from the original drug,” and “low cost = low quality.” While consumer perceptions are shifting, some uncertainty remains, and the challenge of communicating with audiences on these issues can be problematic.
  2. Marketing
    Generics operate with much tighter margins and pricing pressures, hindering ‘full-court-press’ – which is important to the challenge of educating and communicating with consumer audiences.
  1. Trademark/Patent Law
    Trademark law can prohibit generic drugs from appearing like their innovator equivalent. This means branding or designs that are different from what the consumer may expect, creating additional uncertainty and distrust among patients who track their meds by appearance..
  2. Government & Regulatory
    Lawmakers and regulatory agencies around the world have traditionally favored innovator drugs. Recent positive actions and guidance, however, are improving generic access to markets.

Lingering Consumer Misperceptions of Generics
The drug industry as a whole is well aware there is no distinction in performance or safety between generic and innovator drugs. In fact, that’s the principal reason why drug companies fight so hard to protect their IP and keep other firms away from their niche for as long as possible. But despite decades of evidence, some consumers still equate price and quality. A shrinking percentage of consumers remain fearful of side effects that aren’t found in either the brand name drugs or generic equivalents.

With most generics manufactured outside of the U.S., safety perception issues arise when foreign manufacturers are cited by regulators. There is a misunderstanding that the FDA disproportionately cites India’s pharma companies – issuing Form 483s, which list observations related to violations of Good Manufacturing Practices (GMPs).

The FDA is more active in India and elsewhere than in years past – mostly due to the massive upsurge in generics and the bigger chunk of exports to the U.S. With nearly 600 FDA-approved plants (a sizeable portion of whom export to the U.S. market), India (along with China) has increasingly become a focal point for inspections. From LiveMint:

The rise in inspections comes in the backdrop of the Generic Drug User Fee Act’s (GDUFA) implementation in the US in 2012 which sought to hasten generic approvals and eliminate disparity in inspections of US and foreign manufacturing facilities. One-fifth of FDA inspections happen in India and China currently, up from 11% in 2012, said Edelweiss Securities in a February report.

The increased scrutiny is for good reason: India is the world’s largest exporter of generic drugs. The good news is that the percentage of Indian firms cited has been on the decrease over the last year or two due in part to better training and coordination with regulatory authorities.

Well-outnumbering those cited in headlines, there are many companies such as Neuland with exemplary regulatory track records and long histories of working with global regulators. But news headlines highlighting recalls, 483s and import bans absolutely increase consumer – and manufacturing sponsor – concerns.

Emerging Policies to Boost Generics?
In the same pharmamanufacturing.com article referenced above, Langhauser discussed policies that could further drive generic drug growth in the U.S.:

“One prominent solution highlighted in the proposed budget was generic drugs. The proposal included several provisions designed, in theory, to give the U.S. Food and Drug Administration greater ability to bring generics to market faster.”

In spite of challenges, the market penetration of generic drugs continues to grow – playing an increasingly important role in global healthcare. Consumer acceptance has also increased, and regulatory agencies & governments seem to be improving how (and how fast) generics are brought to market.


Neuland Patent Spotlight: Entacapone & Parkinson’s Disease

Treating the Symptoms of Parkinson’s Disease
According to the Parkinson’s Foundation, Parkinson’s Disease (PD) affects about one million people in the U.S., and 10 million worldwide.

While there is no cure for the neurodegenerative disorder, a number of medications are used to treat the symptoms of the disease. It is also common for people with PD to take a variety of medications to manage symptoms.

Entacapone Helps Other Drugs Lengthen their Efficacy
Entacapone – first introduced to the market in late 1990’s – is a selective and reversible inhibitor of the enzyme catechol-O-methyltransferase (COMT). It is used in combination with levodopa and carbidopa (two Parkinson’s drugs) to lengthen their effect in the brain, reducing Parkinson’s disease signs and symptoms longer than the use of levodopa & carbidopa alone.

Challenges of Manufacturing Entacapone
Entacapone – which went off-patent in 2013 – has subsequently seen a number of novel manufacturing techniques emerge. Many of these production methods suffer from a range of problems which can impact commercial viability at the industrial production scale. Among the challenges of common Entacapone production techniques:

  1. The technique may yield the wrong isomeric form.
    Entacapone exists in two isomeric forms. The ‘E’ form is considered the more pharmaceutically active (and therefore more desirable).
  2. Many techniques use piperdine as a reaction base.
    The use of piperdine can lead to the formation of undesirable byproducts.
  3. The technique may use condensation during manufacturing.
    With Entacapone, condensation can be time consuming, which negatively impacts yield and leads to product contamination.
  1. Some techniques may require an extra step of dealkylation.
    Dealkylation of 3-alkoxy entacapone can lead to lower yield and purity.
  2. Some techniques use extra acid and solvent purification steps.
    The use of additional manufacturing steps is time consuming, and yields tend to be very low.
  3. Techniques may use expensive solvents or chemicals which are not viable at scale.
    The use of glycine acetate, for example, is expensive and not viable at commercial manufacturing scale.

Generic Entacapone Delivers Greater Economies of Scale

With Entacapone’s patent expiration, a need arose for generic equivalents to deliver greater economies of scale. (The pricing pressures on generics nearly always make this necessary.) Neuland designed a streamlined process to avoid the use of hazardous and expensive bases and extraneous purification steps.

Neuland’s patented method delivers 90% yields (a boost over traditional methods, which yield only 80%) by reacting 3, 4-dihydroxy-5-nitrobenzaldehyde with N, N-diethyl-2-cyano acetamide in the presence of ammonium acetate. Other advantages of the process include:

  • Economical: cost effective at industrial scales.
  • Eco-friendly: hazardorus & corrosive reagent-free.
  • Simplified handling: does not require special temperature condition monitoring.
  • Avoids impurities: does not lead to the formation of impurities typically found with piperdine.

How Does Neuland’s Process Work?

The method developed & patented by Neuland allows for the commercial manufacture of (2E)-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethylprop-2-enamide polymorphic form A. The process includes:

  • First, 3,4-dihyroxy-5-nitrobenzaldehyde with N,N-diethyl-2-cyano acetamide is reacted in the presence of ammonium acetate to form racemic entacapone.
  • Racemic entacapone is treated with a catalytic amount of hydrogen bromide dissolved in aliphatic carboxylic acid.
  • The (E)-entacapone polymorphic form A is first treated with an alcoholic solvent isolation of the product, followed by further purification with an ester to yield a pure polymorphic form.
  • Racemic 2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethylprop-2-enamide (Entacapone) is prepared via condensation of 3,4-dihyroxy-5-nitrobenzaldehyde with N,N-diethyl-2-cyano acetamide.
  • Resolution of racemic Entacapone is performed in the presence of hydrogen bromide dissolved in aliphatic carboxylic acid.
  • The crude polymorphic form A of (2E)-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethylprop-2-enamide is treated with an alcoholic solvent.
  • It is then purified using an ester such as ethyl acetate.

Entacapone is an excellent example of an off-patent drug where – in order for generic versions to be economically viable – process improvements & efficiencies were necessary. Neuland’s technique checked this box, offering an improved, cost-effective, eco-friendly and easy-to-handle process which yields a substantially purer form of Entacapone at commercial scales.

If you would like to discuss how Neuland can help you overcome your API manufacturing challenges, please contact us.