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:
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.
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):
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 series
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.
With the recent acquisition of Unit III, Neuland’s footprint around Hyderabad continues to grow.
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.)
Earlier 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.
Molecular 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:
Growing 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.
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 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:
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 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.
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:
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:
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:
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.
Properties which can affect an API’s yield, delivery date and purity include:
Want to learn more? Read our earlier post.
Growth in Peptide Demand
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.
…Outsourced manufacturing is expected to grow at CAGR of 6.7% owing to requirements of complex procedures and shift in preference toward outsourcing, which helps in eliminating cost of production.”
Neuland has already witnessed increasing demand for value-added peptides – as well as peptides incorporating non-natural amino acids – corresponding with Grandview’s projected market segment growth trend.
Complex Peptide Purification Faces Challenges
The purification of larger or more complex peptide APIs can be more difficult due to a number of factors, including:
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. Neuland’s proprietary technique – Preparative Reversed Phase High Performance Liquid Chromatography (RP-HPLC) – is used for the cGMP production of Peptide APIs and other complex APIs that cannot be purified through the use of crystallization.
Complementary Complex Peptide Technologies Overcome Purification Issues
Neuland uses all three peptide synthesis techniques: solid, solution and hybrid phase for purification. We also use our own proprietary RP-HPLC purification technology.
In previous posts (here and here) we’ve shared how our surrogate stationary phase in peptide purification is used. From the standpoint of peptide processing efficiency, it is an incredibly effective technique resulting in RP-HPLC loading capacities 7-12X greater than traditional methods.
Neuland’s RP-HPLC technique relies on the use of a surrogate/additional stationary phase comprised of a hydrophobic quaternary ammonium salt bound strongly to C8/ C18 reversed phase columns. This acts as an additional stationary phase or surrogate stationary phase, though such a quaternary ammonium salt can impact resolution.
What’s the Advantage?
Conventional Prep-RP-HPLC loading capacity is 1% of the Total Column Volume. Neuland’s SSP-Prep-RP-HPLC method allows loading capacities of 7% to 12% of the Total Column Volume – an output equal to or greater than normal phase PREP HPLC!
This technology was developed with two types of novel surrogate stationary phases (SSP) for Prep-RP-HPLC that can increase resolution and increase loading capacities:
The RP-HPLC approach to chromatography has applications in a peptide lab that is faced with improving peptide purification efficiency & throughput using existing technology.
How SSP-Prep-RP-HPLC Works
Are you interested in some of the technical aspects of SSP? Here’s a PharmTech Q&A from last year (Reverse Phase Liquid Chromatography Using Surrogate/Additional Stationary Phases). Neuland’s Vice-President & Head of Peptides joined a consultant from CMC Development to discuss the use of a surrogate phase (we use the terms surrogate stationary phase, SSP, and additional stationary phase, ASP, interchangeably).
The PharmTech Q&A explored how to improve separation & resolution between two analytes (the key is to understand precisely how an analyte interacts with the stationary and mobile phases), and some of the key performance features and differences between normal columns and SSP-coated C18 columns.
Questions about peptides? We’re here to help! Contact us to discuss your challenges.
From the day Neuland was established in 1984, our core business and operational expertise has been the manufacturing of Generic Drug Substances.
More specifically, delivering niche, highly-specialized and complex synthetic chemistry services. This has long been our strong suit – earning us the identity of a preferred and reliable source across the pharmaceutical industry.
Our knowledge of synthetic chemistry, process development, controlled supply chain and project management, continue to make Neuland an ideal API partner. Our objectives – and our strengths – as a service provider & partner to the pharmaceutical industry are:
Generic Drugs: Being First-to-Market
The Generic Drug Substance (GDS) space has always been highly-competitive. Our clients’ success is often measured in time. The generic that achieves first-to-market will secure significant market advantages. Project & process efficiency are mission-critical.
With new FDA guidelines recently announced to speed up generic pathways to market, it looks as though annual generic drug market growth of 10.8% remains on track.
From a Zion Market Research report (May, 2017):
“…the global generic drug market accounted for around USD 200.20 billion in 2015 and is expected to reach approximately USD 380.60 billion by 2021, growing at a CAGR of around 10.8 % between 2016 and 2021.”
A 2017 BCC Research report found:
The fact that the generics market is growing is perhaps less newsworthy – at least for us inside the industry – than the ways in which drug development and manufacturing are evolving. From virtual crowd-sourced clinical trials to the advent of QbD & DoE to our ever-expanding discoveries and capabilities in the field of chemistry, drug research & commercialization is in a near-constant state of improvement and change.
Today’s generics space is exciting. New technologies and methodologies are evolving the drug industry, creating new opportunities for API domain expertise and excellence.
Want to learn more about Neuland’s Generic Drug Substances capabilities? Download Neuland’s Generic Drug Substances Brochure (PDF, late 2017).
While there are a number of particle size reduction technologies in use in the pharmaceutical industry today, from our vantage point as an API manufacturer we typically see requests for either jet milling or multi milling. Each has distinct advantages – and also some disadvantages.
But before we turn to a discussion on milling and mechanical reduction, it is important to mention that among the best ways to achieve a particular particle size distribution (PSD) is in-process crystallization. Crystallization offers the potential for extended product shelf life and stability, and should be evaluated with a number of particle size distribution (PSD) techniques using PAT tools (FBRM & PVM) and QbD-DOE (solubility studies – MSZW).
Jet Milling Versus Multi Milling: Determining Which Type of API Particle Reduction Milling Technology to Use
The choice between these two particle reduction milling techniques is driven by the API’s properties, the desired particle size, the API batch sizes and – to some degree – the manufacturing infrastructure & processing costs.
Here are some pros and cons of these two particle reduction techniques:
Jet Milling
Fluid energy – or jet – mills are excellent at reducing particle sizes. For size reduction up to a D90 of less than 10 microns, losses will be minimal – typically 2-3% at bulk scales. Beyond size, jet milling has another benefit: it increases bioavailability for APIs with solubility issues (BCS class 2 or 4).
One downside to jet milling, however, is static. Products produced with jet mills often have high static charges and tend to agglomerate. This can cause poor flow properties, and can lead to problems with blend uniformity.
At larger commercial scales, issues can arise with potential dust explosion hazards (especially with APIs that have low Minimum Ignition Energy – MIE < 3 MJ). Because of this, nitrogen can be used as a fluid with oxygen sensors and in combination with other procedures to safeguard personnel and infrastructure from hazards.
Multi Milling
A multi mill uses variable-speed beaters with different-shaped edges and screens to achieve particle reduction.
Using different screen mesh sizes (e.g., 0.3, 0.5, 1, 2, 3 mm), multi mills are a common choice for de-lumping operations, granulation, or to obtain a coarser PSD of particles. Granulation can be either wet or dry. Among the disadvantages, shear-sensitive products cannot be handled. Its low operation cost, however, and minimal space constraints make it both effective and efficient.
How Each Type of Mill Is Typically Used in API Manufacturing
We’ve found that we most frequently use jet milling with air & nitrogen, yielding a D90 of less than 5 microns, while using multi milling for de-lumping processes. While both are popular techniques, jet milling is best at delivering accuracy and a tight particle size distribution while multi milling remains the most cost-efficient technique.
So Which Reduction Technique Should You Use?
As mentioned above, whichever technique is used – whether it be jet milling, multi milling or in-process crystallization – there may be an impact on chemical properties or stability issues. It is crucial to generate impurity profile data during the API development phase, and monitor for real time or accelerated conditions of the stability data.
In some cases, an alternate methodology or milling fluid (nitrogen or air) may be selected, or packaging conditions may be modified to avoid an impact on chemical properties or polymorph.
Multi milling and fluid energy jet mills are two common techniques used in pharmaceutical API development and manufacturing. Whichever method you choose to control the particle sizes of a drug intermediate, generating data to measure the impact of each method on the API is absolutely essential.
