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Neuland & Generic Drug Substances (GDS)

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:

  • Consistency in product quality
  • Knowledge and expertise with niche chemistry
  • On-time delivery performance.

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 global market for generic drugs should reach $533 billion by 2021 from $352 billion in 2016 at a compound annual growth rate (CAGR) of 8.7%, from 2016 to 2021.

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).


Pharmaceutical Manufacturing: Comparing Particle Reduction Techniques

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.

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Welcome, Unit 3!

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.


QbD and Evaluating ‘What-If’ Drug Manufacturing Scenarios

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.

We also mentioned that QbD is an effective framework for bringing together a collaborative and inclusive team comprised of both chemists & engineers to ensure a successful API scale-up.

A successful QbD implementation, however, demands more than just a collaborative and inclusive team effort. It also requires three key elements:

  • A clear understanding of the target product profile.
  • A determination of CQAs to ensure product quality in accordance with regulatory guidelines.
  • The design, implementation, and optimization of a manufacturing process using risk assessments, design space (DoE), and process control strategies.

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’

  • Ensure a comprehensive project plan has been developed.
  • Implement a periodic review & escalation mechanism for any issues, concerns, etc. relating to process mechanisms (e.g., quality, safety, regulatory, analytical, sourcing).
  • Identify clear roles and responsibilities of the cross-functional team.
  • Ensure that documentation is complete and accurate – from early process development through technology transfer to manufacturing.

A QbD approach to manufacturing process development should include:

  • Identification of the Critical Quality Attributes (CQAs) which impact the drug product.
  • Optimization of the manufacturing process based on knowledge of how material attributes and process parameters will affect the drug CQAs.
  • Identification of relationships between material attributes, process parameters and CQAs.
  • Analysis & assessment of the data to establish product specification ranges.
  • Application of Design of Experiments (DOE) to support process development studies, with the objective of reducing the number of experiments needed during development.

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.


Contract Pharma Project Management & Data Infrastructure

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.

Data Security
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.


Inside QBD: Chemists & Engineers Collaborate on Quality

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.

Chemical Engineers:

  • generate data on the material balance.
  • evaluate energy balances to understand utility requirements for plant scale.
  • select equipment for commercial scale for retrofitting or new, per process requirement.
  • perform risk assessments (Quality, Safety) of unit operations, powder safety characterization studies, HAZOP & & HIRA.
  • evaluate particle engineering (particle size, bulk density, surface area & Polymorph).
  • forecast potential for new technology implementation considering the volume of products, safety threats, troubleshooting activities related to the commercial products, and more.

Chemists:

  • leverage expertise in various types of synthetic reactions, based on both literature searches and hands-on experience.
  • help select the route of synthesis.
  • evaluate the feasibility of the selected route, optimize and validate the process to meet the predefined quality and yield.
  • identify and characterize any impurities which have an impact on quality.
  • perform generation and qualification of reference/working standards.
  • maintain continuous interaction with IP for process infringement with any new process patents,
  • perform process and method validation.

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.


NCEs Versus Generics – Adjusting Project Tactics & Objectives to Maximize Success

Since generic drugs are – on average – 20 to 90% cheaper than innovator drugs (or NCEs), the market for generics has grown considerably in recent years as a means of reducing healthcare costs.

Differences Between NCE and Generic Drug Development
What are the differences between the design of New Chemical Entities (NCEs) and generic drugs, and what do they mean for process development & manufacturing?

For either purely generic or purely NCE companies looking to begin development or commercialize a product in the other discipline, the question is more common than you might think. Companies tend to be narrowly focused on their particular area of expertise (either generic or innovator). It is natural that they would have questions and concerns about commercialization practices outside of their typical operational focus.

Since Neuland works extensively in both areas of drug development & commercialization, these are questions we are quite comfortable answering.

The core difference between these two drug projects can be summed up in the names of their respective FDA filings: NDAs and ANDAs.

NCEs require a new drug application (NDA) with the FDA, while generic drug applications require an abbreviated new drug application (ANDA). The key differences lie in the ‘abbreviated’ nature of generic applications.

The NCE Project Approach
As mentioned above, drugs based on new chemical entities require an NDA filing with the FDA.

With NCE molecules, target product profile identification is critical. During initial project stages, the focus will largely be on the process development of the drug candidate – the key intermediate and target lead optimization steps.

Attention is also placed on process development leading to Phase I, in order to enable adequate supplies of the drug candidate. This focus will shift later to final process development (based on knowledge acquired concerning impurity formation), long-term toxicology, carcinogenicity and Phase II clinical supply.

A common approach with NCEs is to de-emphasize impurity identification during initial phase development and focus on production consistency – and then later concentrate on impurity formation (as well as impurity types), as well as developing effective control strategies.

For Phase III supply, contract manufacturers focus on registration batches and stability studies suitable for use in defining commercial retest dates. The final stage of NCE commercialization is the production of validation batches and launch supplies.

The Generic Project Approach
Generic drug applications are called “abbreviated” in the U.S. because they are not required to include preclinical (animal) and clinical (human) data to establish safety and effectiveness. Instead, a generic applicant must scientifically demonstrate that the product is bioequivalent (i.e., performs in the same manner as the original drug):

“Overall, both EU and US legislation for the authorisation of generic medicines allow for abbreviated applications to be made in the case of generic medicines. In both jurisdictions, pre-clinical and clinical studies do not have to be performed by the generic medicine applicant, but bioequivalence to the originator or “reference” medicine must be demonstrated.

Bioequivalence is demonstrated when the rate and extent of absorption do not show a significant difference from the originator drug, or where the extent of absorption does not show a significant difference and any difference in rate is intentional or not medically significant.

Once approved, an applicant may manufacture and market the generic drug product to provide a safe, effective, low-cost alternative to the public.

Varying regulatory requirements around the world can present challenges for the commercialization of generics. These differences in standards can make it quite challenging for companies to develop a single drug which is simultaneously submitted in all the countries for approval. Because of this, regulatory strategies for generic product development are established between the contract manufacturer and sponsor before work commences in order to avoid any major surprises after submission of the application.

Maximizing Success in Generics & NCEs
The differences in process development methodology between NCEs and generics mentioned above can have a large impact on drug price, safety and performance. With generics, manufacturing costs are often decisive while safety & performance have been previously established.

With innovator drugs, on the other hand, safety and performance for an unproven molecule are paramount. Because of these differences in their characteristics, it is critical to adopt a modified approach based on whether the drug molecule is considered ‘innovator’ or ‘bioequivalent.’


Neuland & Regulatory Excellence

Infographic - Neuland Regulatory track recordWith more than 650 regulatory filings to date, Neuland is committed to total compliance and regulatory excellence. In fact, we consider it our core competency: the application of strong process chemistry to manufacturing in a regulatory compliant environment.

This infographic explores Neuland’s regulatory experience, certifications and track record – from 1984 up through 2017.

Learn more about Neuland’s Regulatory Affairs and Quality Control & Assurance departments.

 


Pharma APIs – What’s On Tap for 2018

Gil Roth, president of the Pharma & Biopharma Outsourcing Association, recently published a piece at Contract Pharma on the challenges and opportunities facing CMOs/CDMOs.

The hot button issues he described pretty much lined up with what I would put in a list of 2018 trends in the API space to watch – rising global protectionism, ongoing industry consolidation and regulatory issues among them. I would also add product differentiation to the list, as it is one of the strategies CMOs/CDMOs are leveraging to address some of the pressures raised by those other trends.

These are issues that often intersect and coincide, and have political overtones. Let’s face it, 2017 represented a political sea change – from the U.S. to Europe and beyond, and for many corporations the world feels like it has become a little bit less predictable.

While Roth’s article focuses on the U.S. market, it also applies more globally. (Brexit hasn’t been a shining beacon for global trade policy.)

First Things First: I’m Echoing Gil Roth on the Value of Predictions

Gil Roth is careful to note what may now become a standard disclaimer across prediction & trend-writing land – and I’m going to agree with him:

“My crystal ball is C-R-A-C-K-E-D, and my backup Magic 8-Ball’s answer to everything is, ‘Reply hazy. Try again later.’”

With that said, here are some of the trends Roth mentions that will bear watching as 2018 progresses.

  • Protectionism
    No one really knows what the impact of increased protectionism will mean for global supply chains – and pharma has become – if nothing else – a truly global supply chain. According to the news, protectionist policies are on the rise – but how it will impact an already global industry is unknown. While there have been rumblings in Washington D.C., nothing has (yet) played out policy-wise. Roth notes in his article:

“A massive influx of pharma dollars could cause those big companies to alter their supply networks…but I think it’s more likely that the money goes to share buybacks, dividends, and acquisitions of U.S.-based targets.”

  • Consolidation
    Here I again agree with Roth – 2017 saw some deals that were ‘consolidation’ at heart, while others were better considered the creation opportunities with untapped potential. Whatever the motivator, industry consolidation is no short-term trend – it has become a preferred growth strategy. There are no signs of it abating, and 2018 will likely continue to deliver news on the pharma M&A front. Some will be done to control costs across the drug lifecycle or increase capacities, while others will aim to expand offerings & market segments.
  • Regulatory
    I typically note that quality issues will be front of center when I sit down to write a predictions-style list, and invariably it is a key focus of industry. Quality always is, or should be. In 2018 though, ‘quality’ will be synonymous with ‘regulatory.’ Over the last few years we’ve seen a marked increase in global regulatory enforcement, and that will likely continue. Global standards are rising, and in some cases regulatory framework synergies are making compliance more universal. It is interesting that global regulatory standards – while increasingly complex – are also working towards a goal of broader universality just as attitudes towards globalism more generally are shifting.

Roth, in his article, points out the impact of GDUFA and the changing regime at the FDA as two things to watch for in 2018.

  • Product/Service Differentiation
    Product differentiation is well underway already. Manufacturing capabilities up-and-down the supply chain – from green chemistry, high potency or alternate route scouting for drug APIs up through novel delivery and packaging solutions – are already delivering differentiated capabilities & products.This has led to increasing specialization – and a 30+ year trend in its own right.  In the article, Roth mentions that “CDMOs talk more about expanding their current facilities, adding services and building more integrated suites of services.”

These are some of the issues that will occupy our attention in 2018 – and surely there are many more.

Read Gil Roth’s piece at Contract Pharma on the challenges and opportunities facing CMOs/CDMOs.

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Synthetic Route Scouting: Factors to Improve API Manufacturing

Synthetic route scoutingSynthetic route selection is a crucial element in API manufacturing. While the requirements of the synthetic process of a drug will naturally evolve during its life cycle, scouting alternate routes early in process development offers you many benefits. Alternate routes have the potential to help you:

  • Improve scalability
  • Reduce chemical or reagent usage and waste production
  • Decrease processing times
  • Improve quality and safety profiles
  • Reduce the number of processing steps or overall complexity

At Neuland Labs, our expertise is often called on to provide custom synthesis and route scouting, and we’ve found that demand for these services has continued to grow as more companies realize the cost, efficiency and safety benefits of process optimization. In this post, we’ll share some of the top things to consider when devising new routes.

Essential Drivers of API Route Scouting

When developing a new synthetic API route, you should look for a route that:

  • Is cost-effective
  • Has the same quality or greater quality than the previously agreed upon route
  • Provides reasonable time to market

While meeting the three criteria above would yield the most benefit, focusing on even one or two of these criteria can provide significant process improvements. For niche products, most companies seek to reduce cost by 2-5% through alternate routes; for generics, much greater savings are sought.

In addition to cost, other factors to consider are batch sizes, throughput of the product, lead time and reducing batch cycle. Shortening the route is frequently a goal, as this one change can singlehandedly decrease cost, time, waste and regulatory constraints.

Ask the Right Questions to Improve Alternate Routes

  • When considering a route change, the first question to ask is why. By changing the route, what clear benefits can be gained in terms of cost, time and availability?
  • The next point to consider is the availability of your raw materials. Are they maximized by your current process, or could an alternate process improve on it? Next, look at the volume of the product in the market. The higher the volume you need to produce, the more benefit you gain from improving the route.
  • Does the manufacturer you work with conduct company product profile matching? This can be very helpful when seeking to make a change. When examining the cost benefit, does it extend to the manufacturer as well as to you?
  • Is the process feasible in the manufacturing plants you’ve selected?
  • Lastly, what alternate green reagents could be used for long-term sustainability of the product? Today, the most innovative routes use the least resources possible and minimize impact on the environment.

Keys to Getting Route Scouting Right

As you consider your options, keep these final points in mind for greatest success:

  • An alternative route should use a strategically inexpensive starting material; using an intermediate from an existing process is ideal.
  • The process used should be robust and require minimal purification. Stages should be telescoped for maximum efficiency.
  • The new route should offer high “atom economy,” creating minimal waste via a greener process.
  • And finally, the developed route must not infringe on any current patents.

By guiding your research with these tips, you should be able to create a new synthetic route that meets your expectations and is sustainable across the drug lifecycle.