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Exploring Neuland’s Therapeutic Segments: Focus on CNS

Drug development is exciting. There’s no getting around it: being a part of an industry which aims to improve human health is a great motivator for waking up and heading to work.

And for those of us lucky enough to work for a contract manufacturer focused on a diverse range of segments, that feeling of satisfaction is often multiplied when we see the results of what we do having an impact around the world.

For this post, we’re sharing graphical representations of the therapeutic areas in which Neuland participates. Our APIs cross many therapeutic segments – from CNS and cardiovascular compounds to hematology, respiratory, rheumatology and more.

For our most recent list of APIs, along with a breakdown by stage of development (commercial, validation, development or evaluation) and regulatory status (US DMF, CEP/COS or DMF filed), download our latest Product List (pdf). Note that some of these products are still under patent protection in countries around the world and will only be available for supply after patient expiry.

CNS Drug Targets

One noticeable attribute of the graphic above is our ostensible focus on CNS drugs. While we do have a substantial number of CNS compounds among our products, any characterization of our work as CNS-related would be a bit misleading. There are two reasons for this:

1.       Neuland actually operates across an incredible diversity of segments, as seen in the graphic above.

2.      Central Nervous System (CNS) therapeutics as a category is exceptionally broad, stretching from analgesics, anesthetics, anti-epileptics and anti-psychotics to drugs for Parkinson’s, MS, cancer, trauma, neurovascular diseases and much more. Within the ‘category’ of CNS, Neuland manufactures APIs for Alzheimer’s, Parkinson’s and migraine as well as antipsychotics, anticholinergics, anticonvulsants, anesthetics, etc. Each of these slivers of the CNS space is practically a market segment unto itself.

That being said, it is important to note that CNS is a huge opportunity. It also happens to be an exceptionally demanding segment for drugmakers. To date, science has gained only a partial understanding of certain CNS conditions, and still must grapple with overcoming the blood-brain barrier – a key hurdle to treatment.

From Advances in Drug Discovery for Central Nervous System Diseases (December 2020):

“Compared to other areas of drug discovery, the clinical failure rate for new drugs targeting the central nervous system (CNS) diseases is even higher. A study from the Tufts Center for the Study of Drug Development found that the success rate for CNS drugs, defined as final marketing approval by the FDA, was less than half the approval rate for non-CNS drugs (6.2 percent versus 13.3 percent) from 1995–2007. Additionally, the mean development time was greater, the time to approval following application submission for marketing approval was longer, and the number of CNS drugs given priority consideration by the FDA was significantly lower relative to non-CNS drugs.”

In 2020, the already-demanding characteristics of CNS development ran headlong into COVID. From A view into the central nervous system disorders market, at nature.com:

“Global sales of prescription and over-the-counter (OTC) central nervous system (CNS) disease-related products totaled $86 billion in 2019. Sales were predicted to grow in 2020, but the field has been one of those hardest hit by the COVID-19 pandemic. The total 2020 forecast fell by $1.4 billion between March and June of 2020, as social distancing and lockdown measures made clinics more difficult to access. But, despite the uncertainties caused by the pandemic, analysts predict that the CNS product market will expand to $101 billion in 2022 and to $131 billion in 2025.”

While drugs to treat CNS disorders face challenges, it is also a segment brimming with tremendous untapped potential. As we continue to improve our understanding of the biology of CNS conditions, novel therapeutic opportunities will emerge.


Green Chemistry by Design (GCbD): The Earlier, The Better for Pharmaceutical APIs

There's a growing consensus in the pharmaceutical industry that drug makers should embrace green chemistry. The last decade of pharma manufacturing has seen green chemistry practices shift from...There’s a growing consensus in the pharmaceutical industry that drug makers should embrace green chemistry. The last decade of pharma manufacturing has seen green chemistry practices shift from aspirational stewardship goals at the lab bench to large-scale bulk techniques that are both cost-effective and environmentally beneficial.

So why has it yet to become universal? Because – like most processes in our industry – the work must still originate at the lab bench.

Generally, pharma companies are pivoting to pursue sustainable manufacturing – but the improvements tend to be only incremental since green chemistry practices are incorporated only as an afterthought.

When implementing green chemistry practices, a process research mindset is significantly more important than a process development mindset. To realize the sustainability benefits of green processes, companies should adopt a Green Chemistry By Design (GCbD) approach.

Green Chemistry: It All Starts With Process Research/Route Selection

There’s always room for API synthetic routes to evolve and become more efficient. When it was first introduced, Quality by Design (QbD) redefined API manufacture, improving efficiencies, reducing manufacturing risk and ensuring more compliant safety profiles. GCbD, a perfect complement to QbD, is designed to achieve the same result in terms of sustainability.

GCbD is not a new concept. In fact, Neuland embraced it years ago. This 2014 presentation at the International Green Chemistry Conference, for example, explored green chemistry and how it’s best approached via process research instead of just process design.

One of our scientists authored a Green Chemistry article (check out page 19) highlighting why the process research phase was critical to a greener and more efficient synthetic API route. The key takeaway from that article is that the process research stage is where the groundwork must be laid for pharma companies that genuinely want to embrace green chemistry.

Does Process Development Matter in GCbD?

  • Research and development are both vital aspects of successful API development. However, process research is crucial when it comes to successfully implementing GCbD. Research tends to involve an academic, proactive mindset that focuses on IP, safety, economy, environmental impact, scalability, and quality. It’s central focus is on emerging API routes.
  • On the other hand, process development piggybacks on the research process to facilitate the development of scalable green manufacturing processes based on the synthetic route designed in the research phase. Process development focuses on the execution and optimization of the identified procedures, processes and techniques.

The two aspects of R&D work hand-in-hand. Developing sustainable and cost-effective processes should begin with process research, and seamlessly hand off to process development.

Challenges with Greener API Manufacturing

The path to a greener API route selection is not always simple, whether for an innovator or generic API. Some of the typical challenges which arise are:

  • Difficulty in minimizing environmental impact. Scouting for an alternative route that promises significant environmental benefits takes time and often a great deal of trial and error.
  • Lower cost-effectiveness due to scalability risks. Even when you pinpoint a greener synthetic route, commercialization might not be feasible, cost-wise.
  • Time constraints. Scouting for better alternative routes tends to extend development time.
  • Difficulty in reducing utilization of resources. One major green chemistry consideration that can’t be ignored is less waste and energy usage. But finding routes that conform to this ideal isn’t always straightforward.
  • Hit or miss approach. Sometimes success at the process research stage is hit or miss, moreso when incorporating green chemistry at the earliest stages. The right-first-time approach isn’t always possible.
  • Poor control over GTI and other impurities. Poor control over genotoxic impurities (GTIs) is a significant health concern that can hinder the development of a greener synthetic route.
  • IP issues. Legal and intellectual property issues can restrict or block process development and optimization.

Process Research and Green Chemistry Parameters

When fusing process research and green chemistry, there are considerations to be made from both the perspective of process chemistry and the environment. Here’s a breakdown of crucial parameters and Here's a breakdown of crucial parameters and the considerations that need to be made to develop a successful and greener API route.the considerations that need to be made to develop a successful and greener API route.

  • Efficient isolation of ingredients. Process chemistry values efficiency in isolations, while environmental considerations favor the production of less energy and waste.
  • Bypassing extreme conditions. Process chemistry considers the ease of scalability and throughput, while environmentally, the primary concern is less waste.
  • Eliminating hazardous reagents and reactions. Reagents and reactions should be safe and scalable from a process point of view. Safety entails both the physical health & safety of team members during manufacture as well as the broader pollution reduction considerations.
  • Streamlining the number of synthetic steps. With process chemistry, the purpose of reducing the number of synthesis steps is to boost efficiency and reduce cost. The environmental approach aims to reduce energy use and waste output, regardless of process efficiency or cost.
  • Limiting oxidation state adjustments. Less time spent on oxidation state adjustments means the process becomes more efficient and potentially reduces pollution from metals.
  • Achieving atom efficiency. Eliminating protecting groups results in high efficiency and better atom economy in process chemistry, as well as less waste for the environment.
  • Using inexpensive and abundant raw materials. Raw material availability is critical to reducing cost and time investments in process chemistry. Environmentally, however, ideal raw materials are those which reduce waste, energy use or other environmental impacts.
  • Maximizing selectivity. As with many of the other bullets listed above, process chemistry seeks increased efficiency and simplified purification methods, while environmental considerations focus on less waste.

As is clear from the list above, the overarching objective of process chemistry (and, by extension, the companies behind the process chemistry) is efficiency. This can run contrary to environmental or green chemistry objectives which focus on waste & energy reduction.

The answer is a balanced approach. GCbD places the process chemistry and environmental perspectives side-by-side to ensure the development of a balanced green chemistry approach with minimum ecological, cost and time impacts.


The Growing Impact of Rare Disease Drugs

AstraZeneca’s $39-billion acquisition of Alexion Pharmaceuticals  joined by Merck’s acquisition of Acceleron for $11.5 billion and other deals, have made the Rare Disease space a destination for Big Pharma this year. Both companies are looking to extend and round out their portfolios of rare disease therapeutics.

DCAT’s Editorial Director, Patricia Van Arnum, referred to the AstraZeneca acquisition asyet another move by a large bio/pharmaceutical company to strengthen its portfolio in drugs to treat rare diseases.” The article makes an excellent point that speaks to the opportunities for rare disease drugs:

“An important development in the pharmaceutical market: rare disease drug approval rates in the US are now approaching non-rare drug approval rates.”

The chart (below) from the FDA CDER Rare Diseases Team shows consistent growth in orphan approvals over the last decade.

It wasn’t so long ago, however, that orphan drugs were relegated to the backwoods of pharma – offering small patient populations, high risk and low reward. As a model, it worked for small and virtual pharma companies – but big pharma kept its distance.

This has changed over the last decade, and the recent acquisitions clearly demonstrate the thinking has shifted.

Rare Disease Therapeutics: Not-So-Orphan Drugs

In 1968, Dr. Shirkey – a pediatrician in the Children’s Hospital in Birmingham, Alabama – wrote about the inequality that he saw in the development of drugs to treat children. He referred to the abandonment, or “orphaning,” of the pediatric population, stating that “[i]t seems unfair that the use of some drugs will be denied based on relatively infrequent use and small sales potential.”

The rest as they say is history – or more specifically, the history of the U.S. Orphan Drug Act stretching back to 1983. Since its passage, the FDA has worked with industry to approve hundreds of drugs for rare diseases. But it’s estimated that about 300 million people worldwide suffer from the approximately 7,000 known rare diseases – 90% of which still have no effective treatment. But progress is happening, albeit slower than anyone would like.

Building on Dr. Shirkey’s description, today there is a clear distinction between rare diseases and orphan diseases:

“Rare diseases, are classified as any disease that affects less than 200,000 Americans. Orphan diseases, including rare diseases, are neglected conditions whose treatments are often not considered profitable due to their cost to develop and limited patient population.”

A Cautionary Note…

The heartening progress that has been made in the rare drug space also earns some cautionary notes. One study, led by a team of University of Michigan and Boston University researchers, looked at how much spending on partial orphan drugs actually goes to treat rare diseases.

“A surprising number of orphan drugs are among the world’s top-selling drugs – including several so-called ‘partial orphan drugs’ approved to treat both rare and common diseases.”

Market Data Forecast also referenced the presence of non-orphan drugs, pointing out that – of the 600 drugs approved for rare diseases since 1983 – 14% have non-orphan approved indications.

In its 2020 Orphan Drug Report 2020, EvaluatePharma mentioned the growing role of Big Pharma in the orphan drug space:

“Big pharma’s recent dominance of the orphan market has fueled calls to reform the orphan drug act in the US. Regardless, orphan drug sales are forecast to increase from $119bn in 2018 to $217bn in 2024.”

Another trend that has emerged – as reported in the Orphanet Journal of Rare Diseases – is progress in certain disease segments. Analyzing 40 years of FDA orphan drug designations, the journal article reported growth in the development of drugs for rare oncologic, neurologic, and pediatric-onset diseases.

Rare Diseases: A Story of Unmet Need & Unique Challenges

Orphan drug development faces a host of challenges. Earlier in discovery & development they tend to be financial, namely, ensuring a stream of adequate funding.

But the biggest challenges facing drug developers for a rare disease compound typically occur later, with clinical trials. Patients must be found among the small population who suffer from the disease, and the difficulties are compounded by the general lack of awareness of the condition among healthcare providers. Clinicaltrials.gov has reported that 32% of uncompleted rare disease trials cited lack of available patients as the reason for their failure.

This low awareness, according to Kezia Parkins in Clinical Trials Arena, “often means that it falls on the patients, who are often the experts in their disease, to educate their own doctors. The article (Rare Diseases 2021: running rare disease trials post-Covid) explains that this lack of awareness creates yet one more challenge: it can be hard for sponsors to identify principal investigators (PIs) – which can then impact the geographic distribution of the study.

A Hopeful Outlook for Orphan Drugs

While it’s difficult to assess what the impact will be of Big Pharma’s interest in the rare disease space, the number of drugs available to treat very small patient populations is growing.

With increasing prevalence of cardiovascular diseases, cancer and metabolic disorders, demand for specialized medicines will remain high in the foreseeable future. But successful rare disease drug development programs will be the ones which remain adaptable and flexible, finding innovative ways to overcome segment challenges.


Deuterated Drug Molecules: Perfecting the Gamechanger

Scientific breakthroughs in the pharmaceutical industry can happen overnight, but it still takes time to perfect a discovery’s applications. Deuterium-labeled active pharmaceutical ingredients (APIs) are one specific advancement that has come a long way.

The chemistry behind their manufacture is established, and some deuterated drug molecules are showing great promise in clinical trials. Manufacturers of APIs (like Neuland) have been working behind the scenes for quite a while to help pharma companies looking to deuterate achieve great outcomes.

Deuterated Drugs – What Are They and What’s the Attraction?

When we speak to people in the industry, sometimes the mention of a ‘deuterated drug’ earns us a questioning stare. The story begins with a chemistry phenomenon known as the “Deuterium Switch.” Deuterium is an isotope of hydrogen because it contains one proton but also has a neutron, which makes it heavier.

Because the two isotopes are close relatives, hydrogen-deuterium exchange is possible at distinct locations of the active pharmaceutical ingredient where carbon-hydrogen bonds are found.

This isotopic substitution – C-H to C-D – gives rise to the kinetic isotope effect, whereby the C-D bond has a much slower reaction rate than the C-H bond. The kinetic isotope effect is more pronounced because of the percentage difference in mass between deuterium and hydrogen (2 versus 1 in mass).

In a nutshell, the extra neutron in deuterium is what makes deuterated drug molecules “bigger and better.” At a glance, we are talking about:

  • increased bond strength
  • chemical stability
  • a slower rate of metabolism by liver enzymes.

Deuterated APIs Sidestep Costly Clinical Trials

The magic of deuterated active pharmaceutical ingredients (APIs) lies in their enhanced pharmacokinetic (PK) profile. The C-D bond is 10 times stronger and has a slower reaction than the C-H bond, delivering superior bioavailability and an improved half-life.

This means that deuterated drug molecules have higher enzymatic resistance, so they have a longer residence time in the body – reducing the need for frequent dosing. Deuterated versions of drugs also have higher efficacy and lower toxicity due to the delayed formation of toxic metabolites.

These traits are why deuteration has been a breath of fresh air for drug discoverers. With deuterated APIs, it’s possible for pharmaceutical companies to neatly sidestep the costly clinical trials associated with a poor pharmacokinetic (PK) profile, high toxicity, and lower efficacy common to traditional drug development.

Applications of Deuterated Drug Molecules – The Developments So Far

The most notable breakthrough in the history of deuterated drug molecules came about in April 2017 when Teva Pharmaceuticals received marketing approval for Austedo. Austedo (Deutetrabenazine) is a deuterated drug version of tetrabenazine that was rolled out to treat tardive dyskinesia and chorea linked to Huntington’s disease.

It has an improved pharmacokinetic profile, including a boost in the half-life of APIs of up to 9 or 10 hours. It’s arrival to market as the first approved deuterated drug was a hallmark improvement in the drug discovery landscape.

Since then, pharmaceutical companies have been conducting clinical trials and filing patents for deuterated drugs at an elevated pace. For instance, Avanir Pharmaceuticals developed a deuterated drug for Schizophrenia which is still in the clinical trial phase. Similarly, drug developer Concert Pharmaceuticals is leveraging deuterium modification against alopecia areata.

But while deuterated drugs are a game-changer, there’s still a lot of ground to cover before the pharmaceutical market is brimming with beneficial heavy-atom APIs.

Navigating the Manufacture of Deuterated APIs

Deuterium is not only the heavier version of hydrogen. It’s also the less abundant counterpart. Deuterium enrichment is, therefore, a vital but challenging process in the synthesis of deuterated molecules.

The process involves separating naturally occurring heavy water from ordinary water, which is more cost-effective because water remains one of the most abundant and freely available sources of deuterium oxide/heavy water.

The separation is commonly done via the Girdler sulfide aka Girdler-Spevack aka the hydrogen sulfide-water exchange process. This is a dual temperature process to facilitate the transfer of deuterium from hydrogen sulfide to water.

Deuterium enrichment of up to 20% is possible over multiple stages of this process. The enriched material is then combined with the appropriate API.

Separation of heavy and ordinary water is also possible through fractional distillation, electrolysis, and other methods, but the Girdler sulfide option is a particular favorite.

The Challenges

While the Girdler sulfide process is popular, it’s hard to ignore the fact that one of the raw materials – hydrogen sulfide, is corrosive, toxic, and has an unpleasant odor. To compound the issue, the separation factor isn’t very impressive.

Catalysts are often used to accelerate the reaction, but it still isn’t budget-friendly since the Girdler sulfide process already has a high energy consumption and requires copious amounts of deuterated sources.

The Future of Drug Deuteration

The good news is that the challenges associated with the extraction of deuterium will lead to new studies, and ultimately to the development of better production routes. As routes improve, we should be better able to eliminate contamination of deuterated raw materials, as well as the need for excessive deuterated sources.

At the same time, drug developers (and their manufacturing partners) should use suitable analytical methods to verify the isotopic purity of deuterated compounds before combining them with drugs. By developing more efficient and cost-effective processes and making other improvements such as the upgrade and renewal of reaction reactors, the challenges of industrial deuterium production can be managed.

Meanwhile, our focus at Neuland Labs remains on leveraging our expertise in deuteration technology to streamline the process of developing and scaling deuterated compounds. If you would like to discuss a deuteration project with us, contact the Neuland team.


Pharma 2020-2021: Much More Than Just COVID

Set aside ‘Everything-COVID,’ and to many outsiders the past 20 months can appear as though the pharmaceutical industry took a sabbatical. Not true, of course…but everything else that occurred in the bio/pharma/medical space was almost entirely overshadowed by the pandemic.

Pharma, biopharma, medical devices, diagnostics and healthcare all stepped into the spotlight in 2020. In some cases, it happened reluctantly, as the media spotlight hasn’t always been a net positive for the overall life sciences & healthcare industries (drug pricing, opioids, and healthcare insurance all come to mind as issues that have left negative impressions of the life sciences/healthcare sector in the past).

In 2020, however, the overall tenor was almost entirely positive as we turned to medicine for salvation. Even under the increased spotlight, however, COVID managed to overshadow most other medical advances.

The fact that 2020 and 2021 saw so much progress outside of the pandemic is itself a testament to a remarkable time. It’s astounding that anything else was even able to happen, as we rushed to understand the virus, find treatment modalities and therapeutic compounds, develop vaccines, reinvent how the entire world did business – all while we adapted our personal lives to massive change and upheaval.

Here are some of the other medical, scientific, and healthcare advances (beyond mRNA vaccines and COVID PCR & antibody tests) that transpired during the heights of the pandemic – but failed to catch our attention.

Digitization and AI
Some technologies or advances slowly weave their way into the fabric of an industry over time. Telehealth and digital transformation fell into this category pre-COVID. Both have now speeded adoption to near light speed. Other advances have also had immediate transformative impact. AI’s use in drug discovery, for instance. 2020 may have been the inflection point where its use became essential for drug developers to maintain a competitive edge.

The use of AI in bio/pharma represents a tectonic shift in the way our industry discovers drugs. Consider the story of German biotech firm Evotec, which recently announced a Phase 1 trial of their new anticancer compound. Evotec partnered with Exscientia, who applies AI to small molecule drug discovery. “Where it might have taken the traditional discovery process 4–5 years to come up with the drug candidate—an A2 receptor antagonist designed to help T cells fight solid tumors—it was found in 8 months by harnessing Exscientia’s ‘Centaur Chemist’ AI design platform.”

Gene Editing Takes Off
CRISPR became (almost) a household word over the last year or so as gene editing received its due. In October of 2020, Emmanuelle Charpentier and Jennifer Doudna received the Nobel Prize in Chemistry for their discovery of the CRISPR/Cas9 genetic scissors which can cut any kind of DNA molecule at a specific location. CRISPR is likely to have a major impact on our ability not to treat but actually cure genetic conditions such as sickle cell disease, hemophilia and genetic immune deficiencies, as well as some cancers.

A Wealth of New Drugs & Drug Candidates
The FDA approved 53 novel drugs in 2020, up from 48 the year prior. 21 of the 53 novel drugs approved in 2020 (40%) were identified as first-in-class. There were an additional 948 generic drug approvals, of which 72 were deemed first-time generics. Through mid-September 2021, we have seen 37 new drugs approved, not counting vaccines.

In addition to COVID-related treatments, the list of novel drugs included an osteoporosis drug which can strengthen bones to prevent breaks, a new statin alternative with fewer side effects and the first drug in a new class to treat HIV-1. Additional drugs were approved for malaria, Ebola, Chagas disease, Parkinson’s, migraines, MS, spinal & Duchenne muscular atrophy, ulcerative colitis, osteomalacia, heart failure, diabetes, growth hormone deficiency, lung, thyroid, prostate, bladder & breast cancers, thyroid eye disease and many more. Drug candidates in 2020 also included an immunotherapy candidate to prevent peanut allergies.

Heart Disease Research
Key advances in the field of heart disease last year ranged from a Phase 3 study for a compound to treat hypertrophic cardiomyopathy to new potential treatments for atrial fibrillation, to the use of SGLT2 inhibitors to help patients with heart failure. The key takeaway from 2020 and 2021, according to the American Heart Association, has been the necessity of applying an interdisciplinary, comprehensive approach to treatment. It’s a lesson that was applied well beyond the cardiovascular space, as anyone following COVID research and drug development can attest.

Advances in Oncology
Cancer research may have slowed down, but the advances that have been made were significant. From the discovery of new genes which help lung and breast cancers grow to development work on cancer detection blood test technologies and the therapeutic targeting of genetic mutations, to a combinatorial immunotherapy for childhood brain tumors, and a drug candidate for triple-negative breast cancer to an upcoming clinical trial of a cancer vaccine, scientists studying cancer made a range of critical breakthroughs in 2020 that will be felt in the years to come.

 

What “under-the-radar” discoveries over the past year-and-a-half caught your attention? Share it with us on Twitter or LinkedIn.


Where Does Pharmaceutical Process Control Start?

The idea of gaining – and maintaining – adequate process control during drug synthesis isn’t new. It underscores the entire point of approaches such as Quality by Design (QbD), and has long been a key element of pharmaceutical manufacturing. Process control is not only a GMP requirement in its own right, but is also a necessary part of process validation.The idea of gaining – and maintaining – adequate process control during drug synthesis isn’t new. It underscores the entire point of approaches such as Quality by Design (QbD), and has long been a key element of pharmaceutical manufacturing. Process control is not only a GMP requirement in its own right, but is also a necessary part of process validation.

Process control refers to more than just the physical steps of synthetic processes. It also involves the analytical aspects of a drug compound. These two facets of pharmaceutical development and manufacturing work hand-in-hand.

Contract Pharma defines In-Process Control (IPC) as:

“Checks performed during production to monitor and, if appropriate, to adjust the process to ensure that the intermediate or API (drug substance) conforms to its specifications and/or other defined quality criteria.”

ICH Q7A guidance is very clear on the range of controls which must be used – from master production instructions to batch production records and specification-settingICH Q7A: From Starting Materials to Finished APIs

In-process controls are governed by International Conference on Harmonization (ICH) Q7A guidance, which explains the importance of such checks: “A reaction step may generate an impurity that may be carried over to the active pharmaceutical ingredient (API), regardless of how far apart that process may be from the API.”

ICH Q7A guidance is very clear on the range of controls which must be used – from master production instructions to batch production records and specification-setting. Among the key attributes for process inputs such as intermediates, detailed production records are required. These include the process sequences which were used to create the material, the range of process parameters, sampling instructions, in-process controls (and their acceptance criteria), and other elements.

Synthesis: Watch Your Inputs

Looking at process control from the synthetic perspective, set up is key. We must keep in mind the specifications of the key starting materials both during the intermediate phase and after the final product is produced.

Developing an effective, reproducible synthetic pathway rests almost entirely on the setup. The sourcing of input materials – whether precursors or intermediates – is a critical step. Remember that when seeking to maintain adequate process control, everything downstream relies heavily on the process inputs. Impurity profiles should be developed with a thorough understanding of raw material sources and their respective syntheses.

Commercial sources of materials are preferred over laboratory-grade materials, as they have higher purities and the requisite scalable processes needed to prepare commercial batches.

Just how important are the starting materials? From Pharmaceutical Technology Europe:

“Chemical processing differs from product manufacturing. For example, the manufacture of a finished product typically involves a molecular entity that is stable under normal conditions and can be stored for prolonged periods without losing its physical and chemical characteristics. Most chemical reactions, however, require very tight controls and close monitoring of their progress because any of several potential result paths may be followed if conditions are not monitored closely.”

Setting tighter product specs doesn’t necessarily lead to a superior drug compound.
Tighter specs might, in fact, yield no product at all. When developing an impurity profile, it’s important to set impurity specifications to meet regulatory standards, but you shouldn’t go too far. When specifications are too narrow or impurity thresholds are set too low, consistent production at scale can become much more difficult.

We recommend a strategy of maintaining broader specifications at first, tightening them as the compound progresses through scale-up and optimization. Once better process understanding is gained, process control can be applied.

‘Watching Your Inputs’ Means ‘Minding Your Suppliers and Knowing Your Ingredients.’
The ICH Q7A guidance also specifies the necessary procedures for the receipt, identification, quarantine, storage, handling, sampling, testing, and approval or rejection of materials.

API manufacturers such as Neuland must have in place robust supplier evaluation programs to ensure the quality of any critical starting materials or intermediates. Supplier evaluation includes a range of criteria, from the company’s regulatory/compliance history and practices to the technical capabilities of its process chemists and quality assurance team.

In terms of the specific input materials, it is important to understand and manage each one according to its traits. At Neuland, for example, the raw materials we use can be sensitive or unstable. Some are moisture-sensitive, others can be sensitive to force, or combustible. Because of these materials traits, attention to containers, storage and handling is essential.

The Finished API: Setting the Right Specs

Earlier, we mentioned that setting specifications that are too narrow (or too low) can result in major headaches at commercial scale. So how do you set the right specs? Many experts agree that it is part-science and part-art, and this is largely true.

The primary objective is to ensure the API synthesis properly controls impurities – including organic impurities, inorganic impurities, residual solvents and – if applicable – microbiological impurities and endotoxins. Equally as important, the process must be inherently reproducible at scale.

In-process controls are a critical aspect of compliant API manufacturing. As the first step of a sound quality program, process controls ensure manufacturers have a thorough grasp of the process and its parameters, and that they are able to identify process & product issues before they escalate.


What to Expect during Pharma Contract Manufacturing Project Onboarding

It is important to distinguish between occupational and process safety hazards. Personal or occupational hazards resulting in injuries like slips, trips, falls and cuts impact one individual in a workplace. Process safety hazards, however, may result in major accidents such as fires and explosions or involve the release of dangerous materials.When your company decides to work with a CMO or CDMO on a drug API manufacturing project, the depth of the onboarding process dictates the success of the project. Onboarding is more than just signing a proposal and being introduced to the team.  It’s a multi-faceted process that ensures everyone has done their due diligence and considered all of the project’s various components.

How to Set Your Pharmaceutical Contract Manufacturing Project Up for Success.

We are frequently asked what a pharma company working with a contract manufacturer should expect during onboarding. In this initial engagement, your CMO should be focusing on building a strong foundation for systems and processes. At Neuland, we call this the Evaluation and Planning phase. The goal here is to understand the marketing and product requirements. From there, a scientifically sound plan – a project roadmap – is created for project development and delivery.

The entire project initiation/onboarding process should involve representatives from every team involved in the project. You want to make sure all stakeholders are taking ownership and understand their roles.

A Focus on the Science.

The focus of any onboarding process should be on the science. The team will review information from literature or technical packages – including reaction conditions, isolation, characterization, quality and yields. As a part of this, they will also need to evaluate the safety requirements and understand the material balance and reaction mechanism for every step of the project. The more the contract manufacturing team can learn early in the process, the more successful the project will be later.

Concurrent with building this process understanding, the team will be identifying the costs of raw materials, relevant vendors, target timelines, licensing information and other logistics pertinent to the project’s successful execution. For example, at Neuland we’re vigilant about mapping out the manufacturing facility and equipment to ensure we’ve planned accordingly.

Address Potential Obstacles.

It’s no secret that no matter how much planning is involved, a project can still get off-track. A critical part of a solid onboarding process is anticipating and addressing obstacles. A proactive approach that identifies potential chemistry, analytical and practical challenges gives the team an opportunity to develop possible resolutions.

We find that this detailed preparation allows us to develop a systematic work plan which provides our customers with a smooth experience – regardless of what happens. This work plan must be approved by all the internal and external stakeholders involved in the process to ensure they understand the scope of the work and are prepared for execution.

In our experience, a collaborative approach is ideal as it leverages each person’s unique expertise. One way to ensure accountability is to use a responsibility assignment matrix. This is particularly helpful when projects include team members from numerous departments – such as Tech Transfer, Development QA, and Analytical.

A Robust CMO Onboarding Process Leads to Delivering Projects On-Time.

A finalized work plan marks the end of the onboarding process and provides a roadmap for the next steps – the first of which we call Feasibility/Familiarization.

This is where the science begins. Experiments are developed & launched in order to start learning about the process and develop recommendations. If adequate planning has been completed during onboarding, the team can quickly move through this phase and onto Step Two, Optimization.

Optimization.
Step Two is the part of the project where we prepare for – and launch – manufacturing. First, we ensure the process is robust and that we are consistently achieving maximum yield at the appropriate quality levels. We then make any final adjustments to processes and align all stakeholders in preparation for the final phase–manufacturing.  With a robust onboarding process, manufacturing should be just as efficient and expeditious as in all the previous steps.

We know our onboarding procedures are rigorous, but we’ve designed them to ensure project success and customer satisfaction throughout the process. We have found that when a comprehensive onboarding process is implemented, the following steps go smoothly and are completed on time.

If your company is considering engaging a contract manufacturing partner, pay close attention to how robust their onboarding process is since it will have a lasting impact during your project.


What Lessons Has Pharma Learned From COVID?

There’s an eye-popping amount of good news for pharma floating around out there. One report claims a ‘Golden decade of unbelievable innovation’ lies ahead. Others point to COVID19 as the ultimate regulatory process-shortening tool – getting vaccines into arms worldwide in under than year.

And yes – this has been a year in which expectations seem to have shifted broadly. When the world shut down, it was quickly re-opened in new ways, using new technologies and processes.

But how many of these changes will be lasting? It’s a safe bet regulators still won’t go to such calendar-condensing lengths for a new hair growth therapeutic!

At the same time, things are likely to change, aren’t they? After all, we’ve solved some very large challenges and many of the lessons can still be applied when we return to a semblance of normality.

There are many opinions on the subject.

McKinsey and Co. recently pointed out:

“An analysis of all new drugs developed since 2000 shows that the mean development timeline—from the start of clinical testing (Phase 1) to approval—is nearly ten years. The same holds true for new anti-infective vaccines: the development of vaccines for the human papillomavirus, shingles, and pneumococcal infections, for instance, clocked in at between nine and 13 years. Most academics and pharmaceutical-industry stalwarts would consider a development timeline of less than five years to be highly unusual.”

This is the way things have always been done.

Drugs generally take ten years and X billion dollars to reach market, with some variability over the years. Costs typically rise, and time-to-market holds reasonably steady. It doesn’t change too much.

And then COVID.

McKinsey put together the following graphic demonstrating the difference between ‘then’ and ‘now,’ comparing the compression of the vaccine commercialization timeline with a sample baseline scenario:

But could this be the new path forward, with drug approvals accelerated to the kinds of timelines we’re seeing with the vaccines?

Let’s explore what experts believe will endure and forever change how we operate in the drug discovery, development, commercialization and distribution space.

Regulatory Fast Tracking – the System Worked

Coronavirus vaccine development and distribution demonstrated a functional high-speed ramp up process, made possible due to fast-track regulatory approvals in key geographies and a public-private partnership approach to investment. Speed was the name of the game, especially when it came to investigating the safety and efficacy of countless compounds and treatment protocols.

McKinsey reports that regulators “increased the frequency and intensity of sponsor engagement,” building on the regulatory collaboration model “used by agencies to facilitate alternate pathways in drug and medical-device development over the past decade.”

Examples of such engagement in the past include “the US Food and Drug Administration’s breakthrough therapy designation, fast-track designation program, and the Real-Time Oncology Review pilot. Similarly, the European Medicines Agency created its accelerated-assessment timetable and guidelines, and Japan’s Pharmaceuticals and Medical Devices Agency developed its Sakigake designation program.”

The pandemic’s expedited development will be studied and evaluated, and new programs or processes are likely to emerge that could help accelerate aspects of the approval process.

Unfortunately, according to McKinsey: “Many of the factors that helped compress development timelines for the COVID-19 vaccine were specific to this global pandemic and likely cannot be replicated in all future drug-development programs.

However, McKinsey agrees that there are lessons to be learned from COVID. “There are lessons companies can take from this experience to potentially reduce development timelines by several years, including revamping their design and execution of clinical trials, their approach to risk investment, and their engagement with regulatory agencies.”

Here are two more aspects of drug discovery, development and commercialization which are likely to prevail based on these newer ways of thinking.

Collaboration
Partnering and collaboration have been a dominant business models in the life sciences for decades, and that won’t change. But what has changed in a post-COVID era is the scale and range – as well as the groundswell of projects that have brought competitors together. We are collaborating more and reaching further. The irony isn’t lost on me, as governments and companies work together to improve supply chain resilience by chipping away at the supply chain globalization.

The breadth of collaboration has been stunning. A Wall Street Journal headline captured it perfectly earlier this year in To Make More Covid-19 Vaccines, Rival Drugmakers Team Up. “Sanofi and Novartis are among the big pharmaceutical companies that have agreed to help make a competitor’s shots. Sanofi and GlaxoSmithKline announced a vaccine development partnership in September 2020. More recently, Merck partnered with Johnson & Johnson to manufacture J&J’s one-shot Covid-19 vaccine.”

Collaboration has flourished not only among drug companies, but with the public health sector, academia, governments and NGOs, and more.

The big question is: will we see a longer-term, continuing collaborative trend in the industry? The challenge may be the lens we use to view things post-COVID. The pandemic has dominated news and sucked a lot of oxygen out of the room. For the last 1-1/2 years, it was healthcare. It was bio/pharma, and diagnostics, and food supply chains, and new social rules & practices. Collaboration in the COVID-era was – much like the use of fast track designations – something of a one-off, a perfect convergence of events.

But a newfound sense of collaboration – not just to share and spread risk, but to speed discovery – has taken hold and is likely to reproduce itself at smaller scale in numerous life science silos. Cancer immunotherapy is one such area, as is cell & gene therapy.

Last month, Bioprocess International predicted the Big Pharma collaborative trend would continue beyond COVID. “Manufacturing collaboration between traditional rivals will be normal post-pandemic say GSK and Merck & Co., both of which are using their capacity to support fellow Big Pharma COVID-19 efforts.”

Others have mirrored the same sentiment. From PharmTech, for example: “The rapid and efficient delivery of innovative treatments through the COVID-19 pandemic has demonstrated the value of collaborations within the bio/pharma industry.”

Digital Healthcare
Digital health is one of those areas of drug industry partnership that pre-dated COVID and will continue to expand and play an increasingly important role in healthcare. With what would seem to be prophetic timing, this 2018 article at Xconomy explored how Novartis, Sanofi, AstraZeneca and JNJ were already exploring the nascent field of digital medicine just a few years before it became a global priority.

Digital health is perhaps one area in which it would be difficult to return to the way things were once done.

  • A one-on-one with your primary care doctor from the sofa, via tablet?
  • Remote clinical trials, allowing more inclusive patient populations?
  • Better data, to alleviate unforeseen problems during drug development and manufacturing?
  • Remote regulatory inspections, to maintain operations during local or global crises?

We’ve added a number of tools to our toolboxes that would be reckless of us to abandon – for patient health, healthcare practitioners and manufacturers.


What are Some of the Key Trends in Analytical R&D Labs?

Five years ago this month, we published a post on emerging analytical R&D trends, discussing key techniques such as Multi-Dimensional Liquid Chromatography, Hyphenated Mass Spectrometric Techniques, Error Analysis, Semi-Micro Methacrylate Monolithic Columns, LC/NMR/MS Integration and Supercritical Fluid Chromatography (SFC). Suffice it to say, 5 years later, most pharmaceutical companies now have many (or all) of these instruments in their labs.

Pharmaceutical sciences have spent the last 2 decades witnessing improvement after exponential improvement – with numerous new techniques and technologies which we now take for granted. This trend has only accelerated over the last five years. We thought it would be a good time to revisit analytical R&D and see what’s on the industry’s radar.

1. Digitization
In our annual report, we pointed to digitization as one of the key pillars of agile business practices to future-proof Neuland and ensure our continued success.

As we inch closer to Pharma 4.0, the industry is focused on ‘all things data’ – from the Internet of Things (IoT), to cybersecurity, to analytics, AI and automation. This ‘digitization’ of healthcare will only continue to accelerate as data-driven results lead to faster time-to-market and lower failure rates earlier in development.

2. Instrumentation
Advances in technology are creating exponential improvements. One key aspect of such advances in instrumentation has been better data integration – the ability to share data across instruments and platforms to speed up results, improve decision-making or better address scientific complexity – whether through more sophisticated workflows and capabilities or via improved accuracy and lower limits of detection.

Equipment is also getting smaller. Portability and miniaturization have become a key factor as labs are increasingly packed with more and more equipment.

Key instruments that have become ubiquitous in the pharma analytical R&D lab?

  • Mass spectrometers are now (surprisingly) commonplace.
  • Chromatography has evolved – upwards in capability, downwards in size (nano-LC) and limits of detection.
  • NMR and x-ray fluorescence are also increasingly playing important roles during analytical R&D.

Many of the advances in instrumentation have occurred alongside the adoption of QbD and PAT – both of which stress orthogonal approaches to analysis. All of these common lab instruments are following the model of smaller, more portable equipment designed for rapid analysis.

Most instrument makers are also in some cases ignoring size as a key driver for some equipment, choosing to focus instead on massive increases in capability – whether speed & volume (high throughput) or precision (e.g., lower levels of detection/increased sensitivity). This concurrent development will continue, driving newer and more capable equipment into even rudimentary labs while further extending the capabilities of higher-end equipment.

3. Improvements in Speed & Time
Analytical scientists spend much more of their time prepping experiments, rather than running them or analyzing the results. Ironically, as sample sizes have shrunk, the time spent on sample prep has grown. This should come as no surprise, given the higher value of some APIs and the smaller, more concentrated volumes and complexity of molecules. These added complexities often demand highly specific (and more costly) analytical technologies as well as the expertise necessary to handle the samples.

To address these challenges, technologies are increasingly adapting to the need for faster processing or turnaround times.

4. Ease of Operation
Speed of analysis is important, but another key factor is ease of operation – opening up the opportunity for additional lab personnel to utilize advanced systems. Analytical instruments are increasingly easy to calibrate and operate. In many cases, one-touch operations have reduced the need for instrumentation training and have broadened the number of lab personnel who can perform complex analyses with minimal background in a tool’s operation. This leads to faster results and less operator error – both critical in an age of increasing compound complexity.

These are just a few of the factors influencing the evolution of analytical R&D in modern pharmaceutical labs. As drug development & commercialization becomes increasingly complex, the instruments & methods used to facilitate development will continue to evolve, further transforming the drug industry.


What Does it Take to Become a Specialist in Late-Phase CMS?

The contract manufacturing industry experienced a significant jump in 2020, as companies realized that outsourcing manufacturing could help improve the bottom line. When a drug transitions from early-stage development to late-stage development, the drugmaker has some big decisions to make. Chief among them:

  • Who are they going to work with to move into critical Phase II of development?
  • Will they keep it in-house if they have the capacity?
  • Will they outsource to a CMO with deep expertise in facilitating and advancing drug manufacturing?

The pandemic made it quite clear that many late-stage life sciences companies are choosing the last option. The contract manufacturing industry experienced a significant jump in 2020, as companies realized that outsourcing manufacturing could help improve the bottom line. As we discussed in our previous post (‘How CMO Expertise Can Solve Key Challenges in Late-Phase Drug API Projects’), when a CMO has the right expertise, they can alleviate bottlenecks in the process – saving valuable time and money.

Many CMOs and CDMOs claim to be experts in late-phase CMS. But what qualities are needed to become a true specialist in contract manufacturing services for late-stage drug development and commercialization?

Here are the top 4 skills your CMO needs to specialize in late-phase CMS:

  1. Data-Driven
    Our earlier blog post on Key Challenges in Late Phase Drug API Projects explained that while the early phases are driven by development, late phases are driven by data. As projects progress through scale-up and into later-stage clinical trials, the goal is to implement an optimized, safe, reproducible manufacturing process.

    At Neuland, we do this using a series of data analysis tools and approaches, such as Quality by Design (for lab optimization) and Design of Experiment (for understanding variables). These techniques, along with others, generate data that influences the manufacturing process. This is why it’s so critical that a CMS team be data-driven, and that there is a clear understanding of how to interpret the data.

    For example, when we launch a late phase project, we begin by studying data from earlier stages to determine how the products will scale.

    Then, as we build out the process, we implement simulations and examine variables, such as solvent volume, temperature, and humidity. We use that data to define operating conditions clearly and to ensure quality, reproducibility and process robustness. With so many potential variables to consider at scale, understanding and being able to effectively use data is a critically important skill.

  1. EHS-Centric Approach
    In early phases, volumes are much smaller, and safety is usually not a significant issue. However, with the much higher volumes found in late-stage small molecule manufacturing, safety is a genuine concern. That is why at this stage, process safety plays a significant role. One of our objectives is to develop safe-by-design processes to eliminate safety liabilities. We constantly assess thermodynamic conditions to prevent runaway reactions before they occur.

    EHS is an underappreciated core capability of large-scale manufacturers, responsible for avoiding potential risks to our team, to business continuity, and to product capacity. It should always be a priority consideration in late-phase CMS.

  1. Effective Management of Yield & Waste AND Comprehensive Knowledge of Mitigation Strategies
    In late-phase development, higher material volumes increase the likelihood of waste disposal costs. Late-phase partners should have a comprehensive understanding of cost-effective processes, waste, and yield.

    We’ve found that our team must be able to bring down the costs –without making cost the focus. In part, this means knowing which lower-cost vendors to use, while also understanding and implementing green chemistry processes to lower cost and waste. Bringing down the cost is also done by paying close attention to yield and waste generation, as well as ensuring reactions are sustainable from an atom economy perspective.

    In the case of one Neuland Labs client, a third-party vendor backed out of supplying materials. We created the compound in-house, substantially reducing costs by using our expertise to design a safe, economical process. Our new process increased yield from 30% to 70% while significantly reducing reagent use and waste generation.

  1. Operational Effectiveness
    In scale-up, there can be many opportunities for wasted time. Teams need to understand which equipment or processes have the potential to speed up or otherwise improve operations. Technology and process development efforts should be geared towards reducing overall cycle times, processing times and reaction times. At the same time, an effective late-phase CMS team should be constantly searching for ways to enhance capacity. In the client example mentioned in #3, we designed a highly effective process that reduced waste, lowered cost and saved time.

These are just a few of the top skills a team needs to specialize in late-phase contract manufacturing services. Of course, communication skills and regulatory experience are vital as well. All of these traits and skills help avoid the risk of lengthening the commercialization process and impacting the patients relying on a drug – risks that few life sciences companies would be willing to take.

To learn more about Neuland’s late-stage capabilities, visit: https://www.neulandlabs.com/capabilities/facilities-overview/