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:
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.
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:
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.
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.
Late last year, Neuland completed the acquisition of an API/Intermediate manufacturing facility in Hyderabad – now designated Unit III.
The Unit III facility is spread across 12 acres and offers approximately 197KL of additional capacity, boosting Neuland’s overall API manufacturing capacity by about 40%. The multi-product facility, with five advanced intermediate & API production blocks, was inspected by the U.S. FDA in 2015. Unit III also provides on-site development, analytical method development, a quality control lab and a pilot plant.
With this new acquisition, Neuland now has three manufacturing facilities and one dedicated R&D center – all of which have been successfully inspected by the FDA (as well as other global regulatory agencies).
The launch of Unit III is very exciting for Neuland, and provides us with significantly increased operational flexibility to better meet the needs of our clients located in nearly 80 countries around the world.
Want to learn more? Contact us today.
In recent posts on the topic of Quality by Design and drug manufacturing, we referenced (here, here and here) the importance of being able to reduce unanticipated challenges by developing deep process knowledge at the lab scale – which aids in transfer to scale-up.
A successful QbD implementation, however, demands more than just a collaborative and inclusive team effort. It also requires three key elements:
The principal objective underlying a QbD approach to drug manufacturing is developing a comprehensive understanding of the various parameters that can impact the drug candidate and ‘what-if’ scenarios to increase the likelihood of ‘right-at-first-time technology transfer.’
Reducing the Risk of ‘What if…’
While identifying the potentially unexpected is a core element of QbD, so – too – is using the information to reduce the risk of those what-if drug manufacturing scenarios.
Key Criteria for Using the QbD Approach to Minimize Process Uncertainties – the ‘What Ifs’
A QbD approach to manufacturing process development should include:
Variations in drug substance processes involving chemical conversions can impact the finished drug product. Some of the parameters involved in these processes are controlled, while some are merely noise. To address variations in the process parameters & CQAs, QbD leverages the concept of design space.
The Importance of Communication & Transparency
For a contract manufacturing partner and the client, project challenges can be compounded by long distances and subpar communications. Because more time and effort is invested with a QbD methodology, we’ve found at Neuland that clear communication is crucial. Much can occur during process development and the shift to commercial drug manufacture, and clients tend to want real-time glimpses into the project.
In this way, any concerns can be brought to a client’s notice in a timely manner. Resolutions can be found that tap the requisite expertise needed to overcome the issues – whether in-house or based on Neuland’s experience with similar molecules. In some cases, the project scope is modified in order to adapt to the client’s product development & launch strategies.
In addition to our weekly (or bi-weekly) reviews with the client, we also give our clients full real-time access to the project status through our Critical Chain Project Monitoring (CCPM) management system to maintain full transparency.
This also seems to be a consensus view. From the 2014 Elsevier publication Specification of Drug Substances and Products:
“As to the questions of how much extra work analytical QbD entails, the answer probably ranges from ‘little or nothing’ to ‘a lot,’ depending on how well QbD is built into the method development and validation process. If it comes as an afterthought, it will surely result in extensive extra work. If QbD is built into the process from the beginning, good risk assessment is performed to eliminate low-value studies, and the results of systematic method development are contemporaneously documented. The impact on time and effort should be minimal while increasing method understanding and robustness.”
This is the protocol we follow at Neuland, and we’ve found that the implementation of QbD from the earliest possible stages tends to reduce the possibility of those undesirable ‘what-if’ scenarios.
For pharma manufacturers, developing rock-solid data infrastructure has become essential. It touches everything we do as a CDMO – from the web-based intranet used for Employee Self Service (ESS), Sales Management and more.
The Rise of Pharma Data Infrastructure
Pharma data is exploding, and the ability to manage and leverage that data has become central to developing and manufacturing drugs. Data has become a disrupter in the pharma industry – one with tremendous potential for companies. Regulators are paying increasing attention to data. Companies want and need data security with their contract pharma partners & suppliers.
Here’s a recap some of the decisions we’ve made at Neuland as we’ve grown our infrastructure – combining our proprietary in-house platform with large, scalable commercial solutions to ensure data compliance.
The Data Engine
For Neuland to best manage both our clients’ and our own data needs, the core underpinnings of our system’s infrastructure needed to have scalable virtualized server stacks with high availability – and be based in a secured data center. We chose SAP ERP to enable effective information transfer across functions.
With SAP, security was one of the drivers that led to the selection. We wanted to ensure consistently high-security standards that would meet the broadest range of pharma client requirements & standards.
Client & Project Management
For project management, we set out to ensure Neuland’s unique project management approach would enable clients to overcome the difficulties involved in outsourcing projects – especially at long distances. We developed ‘GuarD,’ which ensures that our clients receive the highest standards of transparency, flexibility and reliability across the project lifecycle.
The system operates using the principles of Critical Chain Project Management (CCPM) – emphasizing both flexibility & resource availability to maintain broader project timelines. Rather than focusing on rigid scheduling of individual tasks, the system manages towards the collective objective of completing the project within target timelines.
Robust Data Infrastructure Can Yield Pharma Company Benefits
Overall, our data system has been a key part of our success in creating process management efficiencies. When combined with other efficiency measures (e.g., QbD or check out our last post on creating efficiencies by fostering collaboration between engineers & chemists), a robust data infrastructure can translate into significant pharma sponsor benefits.
In a PharmTech webcast, the Neuland team linked up with Dr. San Kiang – Research Professor from the Department of Chemical Engineering at Rutgers University. The objective was a discussion on the importance of collaboration between chemical engineers & pharmaceutical chemists in today’s drug manufacturing environment. This collaboration is important, and is a key element of QbD.
I also recently participated in a Q&A specifically on the collaboration between chemists and chemical engineers during drug development. It is a big issue given the colossal changes happening in the drug industry, perhaps most visibly on the quality & regulatory fronts.
Drug Safety, Efficacy and Feasibility
This collaboration can mean the difference between a viable drug and one that had great potential, but was not practical from a manufacturing standpoint. It is customary to evaluate drugs on two pillars common to regulatory environments – efficacy and safety. In other words, does the drug perform what it needs to perform, and does it do it safely?
In the real world of drug discovery, development and commercialization, however, there is a third equally important pillar: feasibility.
A product can be determined to be safe and efficacious – but if it isn’t feasible to produce (from either an economic or a technical at-scale production standpoint), then it isn’t a candidate for success.
This is especially true since, often before a scalable chemistry process has been fully developed, chromatography (or, more specifically, process chromatography) is used for making materials in early-stage development.
Collaborating Across Scales
When chemists and engineers work hand-in-hand during process development in R&D, processes tend to progress through scale-up easier. There are considerable differences between producing 10 mg batches and manufacturing 500 kg batches, to be sure – and numerous engineering-related factors need to be taken into account. This chart describes the increasing scales in terms of the synthetic process employed – from expedient, to practical, to efficient and – ultimately – to optimal.
This is the role played by the collaboration of engineers and chemists (and the beauty of QbD, in general): ensuring the smooth transition from the expedient to the optimal while developing a safer process with optimized yield and quality.
Because chemists and chemical engineers approach each challenge from different perspectives, there are different areas of expertise needed.
Some of the bullets in these lists involve collaboration between the two fields. Chemical Engineers, for example, are involved in process development quite early and play a role in route selection/ finalization. Across the development phase of a project, both chemical engineers & chemists will work together to understand CPPs & CQAs of the process.
More interactions tend to occur once process feasibility has been confirmed and the generated compounds reach a passing level of quality. Once feasibility has been shown, the engineers will evaluate the process from a safety, health and environment standpoint. They then generate process safety data to create inherently safer processes.
When it comes to scale-up, Engineers and Chemists must work closely together to plan the scale up campaign, demonstrate & confirm feasibility and hand over to manufacturing.