Welcome to Part 2 of our series on managing API particle size. (You can find Part 1 here.) Today we’re talking about some of the new and emerging technologies that can impact API particle sizing. We also discuss in this post how Neuland successfully manages API particle size distribution projects.
As technology continues to develop, there are several new and emerging inventions and methods that can successfully and consistently impact and manage particle size for active pharmaceutical ingredients. Here are four methods which are not only showing promise but delivering on that promise.
Process analytical technology (PAT) such as focused beam reflectance measurement (FBRM) is one of the emerging technologies used to monitor the particle size and chord length distribution online during crystallization. When technology can successfully measure and manage crystallization, companies can speed up the work of creating APIs and get consistent results. Specifically, the Blaze Matrix PAT tool is useful for identifying polymorph transitions and morphology changes during crystallization.
Nanotechnology refers to manipulating atoms and molecules at nanoscale. Currently, many pharmaceutical contract manufacturers tackle the problem of low solubility by reducing the particle size of an API using micronization techniques. However, the demand for further improvements in drug dissolution has led to a shift from micronization to nanonization, as this technology significantly improves bioavailability and therapeutic efficacy.
Some techniques used to produce nanoparticles with precise particle sizes include high-pressure homogenization, nanoprecipitation, and spray-drying. At Neuland, we currently use homogenization and spray-drying to achieve lower particle sizes.
The in-line manufacturing process gives CDMOs the ability to conduct continuous and real-time quality assurance and control (QA/QC), which facilitates immediate adjustments during the manufacturing process. This ensures consistent particle size and improves the overall quality of the final product.
Artificial intelligence (AI) and machine learning (ML) are the newest techniques to manage API particle size. For example, a study published in Pharmaceutics included a list of ways AI and ML are currently being used in pharmaceutical product development.
One of the ways listed is using AI models for particle swarm optimization to optimize particle size distribution, dissolution profiles, and other formulation parameters. Another technique the study explores is artificial neural networks, which use AI/ML to predict the release behavior of active pharmaceutical ingredients (APIs) of various particle sizes under various conditions..
Neuland’s capabilities have helped our teams successfully manage several complex particle size distribution projects. Depending on the project and the materials, we use different strategies to make sure the particle size results in an end product with the characteristics desired by our customers.
In response to the growing need for tighter control over particle size, we launched a dedicated particle engineering lab. This lab contains facilities for crystallization development to achieve desired particle size and polymorphs for NCEs and APIs. It also contains particle size reduction equipment for both dry and wet milling as well as for micronization. The Neuland team has completed several projects that required a specific particle size and distribution. These successful projects necessitated the use of all three of the above-mentioned size reduction methods. We’ve also adopted the latest particle size engineering technologies, including implementing inline and online particle size meters as well as the latest crystallization techniques.
Neuland’s scientific team has conducted particle engineering studies using micronization for products such as Indacaterol maleate (D(90) less than 5 microns) and Ticagrelor (D(90) less than 10 microns). In another project, data generated from experiments with the compound Levetiracetam were used to optimize process conditions to meet the PSD requirement prior to kg scale production.
At Neuland, one of our unique strengths is our expertise in particle size reduction. Some of the particle size reduction techniques we use most often are the hammer mill, comill, multimill, wet mill, and air jet mill. Some products will have specific characteristics such as morphology, bulk density, and flowability crystal habit. Because of these characteristics during development, the lab will thoroughly study the suitable milling techniques and ensure that they can be optimized for scale-up.
We thoroughly study the solubility profile and generate the meta stable zone width (MSZW). Based on the solubility data we often perform various crystallization techniques such as cooling, evaporative, antisolvent, and reactive crystallizations to achieve the desired particle size. If crystallization does not provide the desired properties, then we use various size reduction techniques such as pin milling, hammer mill, comill, multimill, wet mill, and micronization to achieve the desired particle size, flowability and bulk density.
Have specific questions about how Neuland Labs can help you ensure the correct API particle size? Contact us to learn more.
API particle size is a key consideration in manufacturing quality pharmaceutical products, however, particle size is also notoriously difficult to control during manufacturing. Despite the difficulty, it’s essential to get right: particle size and morphology are the two most significant properties in oral solid dosage manufacture and performance, according to research published in AAPS PharmSciTech.
This post explores why API particle size matters and how API characteristics influence particle size. The next post in our series will highlight the emerging technologies for managing particle size.
In the pharmaceutical industry, particle size in APIs is a critical factor. This essential parameter has a direct influence on characteristics such as:
Those characteristics all affect the end patient, but API particle size also matters on the manufacturing side. API particle size, as well as particle size distribution, can affect the ease of the manufacturing process and the yield per batch.
Another primary reason to have precise control over particle size is solubility. More than 80% of the new chemical entities (NCEs) in the current pipeline belong to BCS class II and class IV, making the future of pharmaceutical products look insoluble!
Particle size is an essential characteristic to creating a successful pharmaceutical product, but it’s a notoriously difficult aspect to control during the manufacturing processes. Even a small change in crystallization conditions, such as RPM/agitator/solvent ratios and cooling rates, can lead to significant changes in API particle size, as well as contribute to other property changes.
Another significant factor is changes in an API supplier, which can lead to new particle characteristics. If your company begins working with a new API supplier, be sure to assess the risks leading to changes in particle size. Carefully evaluate whether those changes will affect the drug properties, and if so, to what extent. If the new API size will affect drug properties, see if the method for characterization of particles is still valid.
Managing API particle size is one of the most difficult parts of the manufacturing process. API characteristics exert a profound influence on the strategies employed for managing particle size; therefore, different kinds of particle sizes may require different methods of handling. Here are some examples of characteristics of APIs that can help manufacturers manage the particle size carefully.
The solubility of an API dictates the bioavailability of a compound. APIs with low solubility demand a reduction in their particle size, thereby increasing their surface area and improving drug’s dissolution properties. To manage API particle size, manufacturers can use various reduction techniques, such as micronization, different types of milling, and nanosizing. These methods can be used to decrease particle size and increase solubility.
Crystalline structure plays a pivotal role in bioavailability. Amorphous APIs (devoid of crystal lattice) exhibit higher solubility and bioavailability compared to their counterparts. Therefore, preserving a desired amorphous state becomes critical and provides a precise control over particle size.
APIs with inherent chemical reactivity can pose unique challenges in maintaining particle size during manufacturing processes. Different conditions, such as lump formation during drying or a hygroscopic nature, can lead to the formation of an agglomerate, which frequently results in a higher particle size. To manage API particle sizes for chemically reactive compounds, manufacturers must control environments by using dehumidifiers and specialized equipment to ensure integrity of the final product.
Managing the size of API particles is typically a complex process, but certain API characteristics are even more challenging to manage than others. Here are four characteristics that can make particle-sizing projects more difficult.
Many projects involve products with a single tier of PSD requirements. For example, a product may be d90 < 10 microns, which means that 90% of the particles are 10 microns or less. As with any pharma project, challenges can arise even during single–tier requirement products.
Projects become more challenging with two-tier requirements, in which materials are required to meet two distinct specifications. As the specifications move to three tiers, the difficulties become even more magnified. Controlling the particle sizes—for example, matching between the various tiers of d50/d90—can require the study of a combination of crystallization process and different particle reduction and sizing techniques.
Polymorphism refers to the ability of a compound to exist in multiple crystalline forms, known as polymorphs. Polymorphs have variations in physical properties such solubility rates, melting point, density, flowability, and particle size distribution. One polymorph may have larger particles or dissolve more readily compared to another.
Crystallization may also make an API more challenging. Crystallization challenges can involve precise temperature, solvent selection, and other parameters, thereby adding an extra layer of complexity to the process. Since crystallization can affect different pharmacokinetic properties, extensive studies are required to ensure the selected form does not change its particle size or stability over time. All these necessitate precise control over the manufacturing process to achieve consistent particle sizes.
APIs which are hygroscopic in nature can absorb water molecules. They are prone to moisture uptake from environmental air conditions leading to changes in the particle size. This can create agglomeration or clumping, causing non-uniform PSD. Moisture can also lead to the degradation or physical instability of the API.
Hygroscopic APIs are difficult to process for size reduction, as the materials tend to absorb the moisture and not have the flowability to pass through the mill. Manufacturers should ensure controlled environments with low humidity levels along with moisture-resistant packaging and desiccants to maintain desired particle size.
Stay tuned next month for part two of our series on API particle size. If you’re currently having challenges managing particle size and have questions, contact us here.
Selecting the right pharmaceutical contract manufacturing partner for Phase 3 clinical and commercial supply is challenging. There are several critical qualifiers you need to consider:
Here’s how Neuland and Karuna Therapeutics partnered to meet the company’s clinical and commercial supply objectives.
Karuna Therapeutics is a biopharmaceutical company developing drugs for people living with psychiatric and neurological conditions. When Karuna and Neuland started discussions in early 2019, Karuna had an abbreviated timeline to scale up an NCE API, produce clinical trial quantities, and begin commercial manufacturing to support a combination CNS drug.
Tackling Challenges to Meet Phase 3 Clinical Trial Deadlines
Karuna and Neuland started working on the project in mid-2019. The scope of work included:
Tech Transfer: Translating Process Chemistry
It’s widely known in the industry that technology transfer can be a source of complex problems. CROs and CDMOs who focus earlier in the drug development cycle (preclinical through Phase II, for example) tend to be less familiar with process scaling issues that may arise at late-stage clinical and commercial scales, such as large scale hazardous chemistry. This is something that often is not taken into consideration during early R&D or process development. Raw material sources specified in early process design (discussed below) can be another potential pain point as procurement needs shift to bulk quantities.
Managing Supply Chain Risks: Backward Integration Via In-House Synthesis
Karuna – like other forward-thinking pharma companies – saw the need to have robust global Regulatory Starting Material (RSM) supply chains. Cost, delays, shutdowns, backed up ports, insufficient trucking capacity – the industry was surrounded by logistics risks and Karuna needed to ensure supply security.
Due to unforeseen challenges with the original RSM, Karuna and Neuland decided it would be advantageous for the client if Neuland developed capacity for RSM. By doing so, Neuland backward integrated production of the RSM, allowing for high quality and cost-effective manufacturing, and also established three domestic secure sources for the RSM’s starting material.
Handling Facility Shutdowns and Global Logistics
Shutdowns due to COVID outbreak were a particularly worrisome supply chain issue. When China closed, and India moved to follow suit, Karuna asked Neuland to ship available material to secure it in a GMP warehouse in the U.S. for its ongoing clinical trials.
At the time, global logistics were in a state of chaos, but Neuland’s expert logistics team ensured sufficient material was pre-positioned in the U.S. to meet the Company’s immediate clinical needs.
Complex, Hazardous Chemistry at Scale While Improving Yield and Speed
From a process design standpoint, handling large volumes of sodium cyanide poses risks. The route development team at Neuland was able to eliminate multiple hazardous reagents and large-scale reaction conditions while increasing yield and reducing cost.
The original process design produced low yields at each of its four stages. A cross-functional team at Neuland evaluated this 4-stage process, identified potential gaps, and created greener, more efficient and cost-effective processes.
Other Project Highlights Included:
Comprehensive Team Approach
Quickly approaching timelines required frequent collaboration from Neuland and Karuna, including process chemistry, analytical development, process engineers, Quality, EHS, production, and export logistics teams. A collaborative approach ensured seamless information-sharing which accelerated and simplified scaling.
Given the global and process-related complications – the project advanced swiftly.
Successful Design, Development and Launch
While API projects often feature one or two particularly strong outcomes, this project hit nearly every high point imaginable – from successful scale-up on abbreviated timelines, improving cost efficiencies, meeting regulatory objectives, and improving the client’s (and our own) supply chain security.
Specialty drug APIs are both a blessing and a challenge for pharmaceutical companies. They are essential for treating patients and saving lives. The demand for them is high, which promises revenue growth. However, even in the extremely lucrative market of APIs — the API market was valued at around $228.5 billion in 2022 and is expected to expand at a 6.5% CAGR through 2023 — the hurdles around specialty drug APIs remain. The high demand has drawn many companies to invest in these products, but many find they aren’t prepared to properly scale specialty APIs due to the difficulties in the process.
In this article, we explain some of the common challenges that drug companies face when working with specialty drug APIs, as well as some ways to mitigate those challenges with the right contract manufacturing partner.
Specialty drug APIs have high complexity and diversity of chemical structures and synthesis routes. Companies must have a team with deep expertise and experience in organic chemistry, analytical chemistry, process development, and scaling to manufacture these products. Even if a company can find the right talent, the synthesis is still complex. Each drug is different and requires a unique, detailed mapping of how process conditions may affect product quality.
One effective approach to tackle this complexity is to outsource development, scale-up, and manufacturing to a contract manufacturer who specializes in these kinds of drugs. Collaborating with an organization such as Neuland, which is equipped with a dedicated state-of-the-art R&D center with around 300 scientists skilled in complex chemistry and process development, ensures your organization has access to the requisite expertise and resources for success.
Another challenge facing pharmaceutical companies is the stringent quality and regulatory requirements for specialty drug APIs. These drugs demand rigorous testing, validation, documentation, and compliance with global standards such as USFDA, EMA, PMDA, etc.
The regulatory and quality requirements become even more complex for global companies. Different countries and regions have separate guidelines about the manufacturing of APIs and highly active drugs (for example, Europe’s EMA, China’s CFDA, Mexico’s COFEPRIS, USFDA, Canada’s Health Canada, Brazil’s ANVISA, and India’s CDSCO).
ActaBiomed, a clinical medicine journal, published an article that suggested that the best way to overcome these regulatory challenges is to standardize requirements across countries as well as across drug types. Many regulatory bodies use words like “some” and “certain” when describing which regulations apply to which kinds of chemicals that must be manufactured separately. Harmonization among countries and establishing a common scientific language could significantly increase manufacturing efficiency and ease regulatory confusion.
Until then, how can drug sponsors manage the complexities of global regulatory bodies? One solution is to work with a manufacturer, such as Neuland, with expertise in specialty drug APIs. Manufacturers with this expertise can synthesize, manufacture, and supply APIs and advanced intermediates for specialty drugs, especially those that target rare or orphan diseases. These companies can also offer their customers cost-effective synthesis, IP protection, and regulatory support.
The high cost and risk of developing and manufacturing specialty drug APIs is another challenge for pharmaceutical companies. These APIs often require significant investments in R&D, infrastructure, and equipment. Even when an organization successfully develops a specialty drug API, there are still many expensive risks, such as:
Two recommendations on how pharmaceutical companies can address risk and cost challenges include:
Neuland minimizes risks with our dedicated mini plant for scaling up new products. We also have a process safety lab for evaluating the hazards of chemical reactions. Neuland conducts safety studies to assess the potential risks associated with the manufacturing processes used to produce drug substances and to implement appropriate measures to mitigate these hazards and ensure the safety of workers, the environment, and the final product.
Development of specialty drug APIs is also hampered by the intense competition and innovation in the Specialty Drug API market. The industry requires constant monitoring of the latest trends, technologies, and opportunities for differentiation and value addition.
One contributing factor to the fierce competition is the increasing complexity of novel targeted therapeutics and the lack of in-house manufacturing expertise. According to researchers at Imperial College London, this has led to an increase in mergers and acquisition (M&A) and outsourcing strategies, making it harder for smaller companies and startups to succeed against global corporations with more funding.
Neuland’s core values help our clients succeed in this competitive environment. These values include customer-centricity, reliability, accountability, ownership, openness, and transparency. We also offer a no-compromise policy of not competing with our customers for finished products.
Contact us today to see how Neuland can help you overcome barriers and launch a successful specialty drug API product.
To be successful, pharmaceutical innovators and biotech organizations need to optimize production and achieve higher yields of their active pharmaceutical ingredients to make products more cost-effective. To realize these results, proper scale optimization is vital.
To learn more about how scale optimization projects unfold and how they can be achieved most effectively, we sat down with Dr. Mahender Rao Siripragada, president of R&D at Neuland Laboratories.
A: Basically, scale optimization involves improving and optimizing the manufacturing process of pharmaceutical products, with the goal of increasing production efficiency, reducing costs, and ensuring consistent product quality.
Key aspects of every project include a comprehensive analysis of the existing manufacturing process, an assessment of scale-up considerations, process optimization to maximize productivity and minimize variability, technology evaluation, risk assessment and mitigation, validation and regulatory compliance, implementation, monitoring, and strategies to ensure continuous improvement over time.
In addition, there’s a lot of multi-departmental collaboration throughout the entire project. Our cross-functional teams include process engineers, scientists, quality control experts, regulatory specialists, and manufacturing personnel to ensure success.
A: Process research and design are the most critical stages because they ensure the development and manufacturing of high quality, safe and effective drugs.
Process research involves exploring new technologies and methods that can be used to manipulate chemicals in compounds to create new drug products. This may focus on developing new methods of synthesis or improving existing manufacturing processes.
Process design, on the other hand, involves taking the results of the process research and designing processes that can efficiently and effectively produce the API on a large scale. That involves selecting appropriate equipment, defining critical process parameters, and setting quality standards that ensure that each batch produced is a high quality during the process research phase. Chemists and researchers work together to understand the chemistry of the compounds and identify potential routes to synthesis. They also use computer modelling laboratory experiments.
Another approach is to enhance the synthesis process to ensure that it is safe and effective. Process engineers and chemists work together to design the manufacturing processes for the API determine where it can be optimized and establish critical process parameters — the points in the manufacturing process that have the most significant impact on quality. These must be carefully controlled to ensure the safety and efficacy of the drugs produced.
A: That depends on the specific drug product being produced and the scale of production required. If the current process is inefficient or produces a low yield, it may require significant optimization. On the other hand, if the manufacturing process is already fairly efficient, the scale optimization may be more focused on fine-tuning the process to improve yield or reduce costs. Scale optimization can also be an ongoing process as new technologies and methods are developed.
A: Route Scouting Scale optimization is about making an existing active pharmaceutical ingredient manufacturing process more efficient. It aims to improve the process so that it yields the desired outcomes while minimizing costs and environmental impact, as well as ensuring that the produced batch meets regulatory requirements.
on the other hand, is focused on identifying new ways of synthesizing an API. This happens in the early stages of development when researchers aim to determine the most efficient and cost-effective process. In route scouting, various options are proposed and explored to identify the most optimal way.
In summary, scale optimization focuses on improving an existing process, while route scouting aims to find a new and better process. In both cases, the goal is to ensure the optimization of manufacturing processes, resulting in high quality drugs that meet regulatory requirements.
A: There are quite a few. I’ll try to summarize them quickly.
At the top of the list are process control and quality assurance. These are crucial to maintaining consistent quality in every pharmaceutical manufacturing process. Developing robust process control strategies and implementing quality assurance measures throughout the chemical process development are demanding but essential tasks. They include monitoring critical process parameters, implementing analytical techniques, and ensuring batch-to-batch consistency.
Ensuring the safety of the chemical processes and compliance with regulatory requirements are also critical challenges. Pharmaceutical companies must adhere to strict quality standards, Good Manufacturing Practices (GMP), and environmental regulations. It’s our job to ensure they can demonstrate the safety and efficacy of the processes and products to regulatory authorities.
Moving from laboratory-scale to large-scale production is another significant hurdle. Every process must be scalable to meet the demand for commercial production while maintaining product quality and consistency. Factors such as equipment design, raw material availability, and process control need to be considered during scale-up.
Then there’s time to market. The pharmaceutical industry is highly competitive, and getting new drugs to market quickly is essential. Developing and optimizing chemical processes within tight timelines requires efficient project management, collaboration between different teams, and effective communication.
Cost is always a major concern. Developing new chemical processes for pharmaceutical manufacturing can be expensive. In the first place, the industry must invest in research and development, equipment, facilities, and skilled personnel. The cost of scaling up a process from the laboratory to commercial production can also be significant.
Developing efficient and high-yield chemical processes is essential in order to optimize production and minimize costs. Pharmaceutical companies aim to maximize the yield of the desired product while minimizing waste and by-products. This requires expertise in process optimization, reaction engineering, and separation techniques.
New chemical processes involve intellectual property considerations. Pharmaceutical companies invest significant resources in research and development, so protecting their proprietary knowledge and innovations is crucial. They must navigate patent laws and ensure that their processes remain confidential and secure.
Last but certainly not least is environmental impact. Sustainability and reducing the environmental footprint of pharmaceutical manufacturing is gaining increasing importance. There’s growing demand to develop chemical processes that minimize waste generation, energy consumption, and the use of hazardous materials. Companies need to explore greener alternatives and adopt environmentally friendly practices.
Addressing these challenges requires a multidisciplinary approach, involving chemists, engineers, regulatory experts, and other professionals to overcome technical, regulatory, and operational hurdles. Collaboration between industry and academia can also play a vital role in tackling these challenges and advancing the field of pharmaceutical process development.
A: Neuland’s vast technical and scientific expertise in route scouting is helping our partners identify the best, most feasible and cost-effective routes of synthesis for the API they want to manufacture. We bring strong experience in supply chain management to the process, which helps identify the best options for potential vendors. Our dedicated analytical team enables feasibility studies to be completed very quickly.
The advantages of strong technical expertise, seamless coordination between cross-functional teams, along with the quality policies adopted by our management have established Neuland as one of the best API/CMS manufacturers in the world.
Contact us today to discuss your next scale optimization or route scouting project.
The development of drug substances heavily depends on a thorough and precise understanding of its different processes. One of these critical steps is crystallization, which has a significant impact on the properties of active pharmaceutical ingredients (APIs). By optimizing the approaches to crystallization, we can improve the stability, solubility, and bioavailability of APIs, which are essential factors in the successful development of effective drugs.
What is Crystallization?
Crystallization refers to the transformation of molecules or atoms from a liquid or gaseous state into a solid state. This process results in the formation of crystals, which are pure substances with atoms arranged in a well-defined and rigid crystal lattice to minimize their energy state.
The properties of the solid state, including the size, shape, and internal structure (morphology) of the crystals, can have a significant impact on the performance of a drug.
In drug development, various types of crystallization processes are utilized, such as cooling, evaporation, and reactive crystallization. Each of these methods offers distinct advantages. The selection of the appropriate process depends on factors such as the nature of the drug, required purity levels, and specific physical and chemical properties of the active pharmaceutical ingredient (API).
Challenges in Crystallization
Crystallization, an essential aspect of pharmaceutical manufacturing, presents a range of obstacles. Its complex nature, combined with the need for precise outcomes, demands specialized expertise and resources.
Consistency is vital for the development of active pharmaceutical ingredients (APIs). It is necessary to achieve consistent results in successive crystallization runs conducted under identical conditions. However, due to the process’s sensitivity to even slight variations in factors like temperature, supersaturation levels, and stirring rates, maintaining reproducibility is often difficult.
To achieve reliable results, your contract manufacturing partner must possess expertise in the crystallization process. This expertise enables them to select the appropriate process parameters, facilitating consistent production of crystals with the desired size, shape, and purity while minimizing downstream processing issues.
The shape and size of crystals, known as crystal morphology, can significantly impact a drug’s physical and chemical properties, including solubility, stability, and bioavailability. However, predicting and controlling crystal morphology is a complex task that necessitates a profound understanding of the solute-solvent interaction, nucleation and growth rates, and the conditions of the crystallization process.
Even trace amounts of impurities can disrupt the crystallization process, leading to issues such as alterations in crystal structure, hindered crystal growth, and even failed crystallization. Controlling impurities originating from both the solute and the solvent is a crucial challenge in pharmaceutical crystallization.
Laboratory-scale crystallization often does not seamlessly translate to larger-scale production due to variations in parameters like mixing and heat transfer. The scale-up process typically requires iterative adjustments and is time-consuming, as careful optimization is necessary to maintain product quality and process efficiency.
Polymorphism refers to a compound’s ability to exist in multiple crystal structures, each with distinct physical properties. While polymorphism offers opportunities for optimizing drug properties, it also presents challenges in controlling which polymorphic form is obtained during crystallization. Undesired polymorphic transformations can occur during storage or processing, negatively impacting the drug’s properties.
Crystallization Process Steps
Each step in the complex crystallization process plays an essential role in shaping the final product.
Selection of the appropriate solvent is the key first step in the process. You must consider solubility and safety when choosing the proper solvent.
Crystallization begins once supersaturation, a state where the concentration of the solute surpasses the solvent’s ability to dissolve it under specific conditions, is achieved. This imbalance is typically attained by manipulating temperature, reaction, evaporation, or pressure to exceed the solute’s natural solubility in the solvent. The delicate dance of this manipulation is integral, as the degree of supersaturation influences both the rate of nucleation and crystal growth that follows.
Following supersaturation, the solution undergoes nucleation. Here, solute molecules or atoms dispersed in the solvent start to congregate into stable clusters, forming a nucleus. This aggregation is the seed from which a crystal will grow. Precise control over nucleation is crucial, as the number of nuclei formed will dictate the number of crystals and inversely affect their size.
Once the nucleus forms, the stage of crystal growth commences. Additional solute molecules continue to deposit onto the existing nuclei. As they arrange in a defined, repeating pattern, the crystal begins to grow.
This stage is key to determining the crystal’s size, shape, and quality. Several factors can influence this growth, such as temperature, agitation, and the rate of supersaturation reduction. Striking a balance between development and nucleation is often the key to achieving the desired crystal size distribution.
The final step in the crystallization process is removing and isolating the crystals from the remaining solution. This isolation is typically accomplished using filtration or centrifugation, followed by a drying step to remove residual solvent. It’s important to handle the crystals gently during these steps to prevent damage or alteration to their carefully grown structures.
Common Crystallization Parameters and Transformations
Understanding the parameters involved in crystallization is vital for process control and optimization. Some of the common parameters include supersaturation levels, temperature, and pH. Monitoring and managing these parameters helps ensure optimal conditions for crystal formation.
Transformations are changes in solid forms during or after crystallization. They could involve polymorphic transformations (changes in crystal structure), amorphous to crystalline transformations, and desolvation (loss of solvent from solvate crystals).
Neuland’s Expertise in Crystallization
Our research team at Neuland focused on enhancing the physicochemical properties of Voxelotor, an API utilized for treating sickle cell disease. Voxelotor is a Class II drug with poor solubility. To address this issue, we employed crystallization techniques, resulting in significant improvements.
The outcomes of our study, titled “Physicochemical aspects and comparative analysis of Voxelotor and its salt and cocrystal,” were recently published in the Journal of Molecular Structure. The cocrystal of Voxelotor with Succinic acid exhibited notable enhancements in solubility and stability compared to the free base form. This work highlights our unwavering commitment to advancing drug development by employing innovative crystallization approaches.
Crystallization impacts multiple aspects of a drug’s quality and performance. Navigating the complexities of this process requires a deep understanding of crystallization chemistry, expertise in process control, and the ability to solve inherent challenges.
Contact us today if you want to improve stability, solubility, and bioavailability.
There have been significant changes in the pharmaceutical industry over the past few years, and some of them have led to significant breakthroughs. One example is the growth of deuterated chemistry in the biopharma space.
With demand soaring for new drugs and medications, deuterated drugs can address a wide variety of problems at an affordable price. Deuteration chemistry has become a popular emerging frontier with tremendous potential to provide medications with improved pharmaco-kinetic and toxicological profiles.
What do pharmaceutical companies and product managers need to know about deuterated drugs, and how could they help you improve your processes?
What Is Deuteration Chemistry?
First, it’s important to discuss the meaning of ‘deuteration chemistry.’ It refers to using deuterium instead of hydrogen in the molecular structure. Hydrogen, the first element on the periodic table, has one electron, one proton, and no neutrons. Deuterium is similar to hydrogen in that it has one proton and one electron, but it also has a neutron. This makes deuterium an isotope of hydrogen, but the extra neutron adds some additional weight to the atom. Deuterated drugs exhibit superior pharmaco-kinetic or toxicological properties due to stronger deuterium–carbon bonds.
The incorporation of deuterium further leads to increased chemical stability, which is reflected by its slower rate of metabolism in the human body when ingested.
What Are the Advantages of Deuterated Drugs?
There are some significant advantages of deuterated drugs. One of the immediate benefits is that deuterated drugs typically possess a much longer half-life (e.g., the amount of time it takes the body to metabolize the medication).
The C-D bond is approximately 10 times stronger than the C-H bond, so it takes much longer for the body to break down the medication. A deuterated drug is much more resistant to enzymatic cleavage, which means that deuterated drugs will stay in the body for a longer amount of time.
Some of the main advantages of a longer drug half-life include:
Deuterated drugs can reduce expenses during the research process and help bring new medications to the market more quickly.
Traditional drugs with a C-H bond can fail testing for a variety of reasons, including:
Deuterated drugs can sidestep these issues because they are more efficient and less prone to side effects. They also have access to streamlined approval processes with the FDA. Because many of these issues can be avoided with stable deuterated drugs, clinical trials tend to focus almost exclusively on pharmacokinetics and toxicity, streamlining the approval process and helping companies get new medications to the market more quickly.
Where Does Deuterium Come From?
Clearly, there are a lot of advantages that deuterium can provide in the world of pharmaceuticals, but where exactly does it come from? It is true that hydrogen is significantly more common in the environment than deuterium, so deuterium enrichment is a vital part of the manufacturing process. Heavy water (D2O) produced through the deuterium enrichment is the most convenient source of deuterium.
We manufacture advance deuterated reagents, starting from heavy water (D2O) and deuterated methanol. This process has multiple stages, and we combine the result with the appropriate API to provide our clients with the target compound.
Neuland and Deuteration
Because of the stronger carbon deuterium bonds, deuterated drugs often demonstrate superior pharmacokinetic and toxicological properties. A handful of deuterated drugs have been approved, and many clinical trials continue to move forward.
Neuland Labs is proud to be an industry leader in this developing niche, and is a commercial supplier of deuterated APIs. If you would like to learn more about how we can help you take advantage of deuteration chemistry to improve a therapeutic API, contact us today.
Respected Irish business Niall FitzGerald once said, “Sustainability is here to stay or we may not be.” A supporter of sustainable business initiatives in Europe, he has also pointed out that capital markets are mass migrating towards higher ESG scores.
The pharma industry is one of the world’s largest, accounting for nearly $1.5 trillion in revenue in 2021. It has an equally large environmental footprint, consuming enormous volumes of water, and generates chemical and material waste. Pharma is also 55% more emissions-intensive than the auto industry. As much as 80% of this consumption has been attributed to manufacturing operations.
To truly achieve sustainability, the industry will need to rethink and transform manufacturing processes – from product design to distribution of goods.
If you’re thinking “yes, we need to get started doing this,” here’s some good news: the push to discover new approaches is already well underway – both here at Neuland and in the broader drug development and manufacturing industry. Breakthroughs – like the examples below – are often refined, adapted, examined and re-examined… some may become established SOP. These three examples impact areas critical to the pharma industry, spanning energy consumption, resource utilization and waste reduction.
Researchers at the University of California Santa Barbara have developed a process for reducing carboxylic acids to aldehydes and alcohols in water, without reagents, precious metals and specialized ligands.
Researchers in Italy and the UK have developed a process which uses green reagents to selectively remove metals like nickel, then copper, silver and gold from various discarded electronic devices for re-use as catalysts in pharmaceutical chemistry.
According to Fierce Pharma, global consulting firm Oliver Wyman reports that pharma companies are making commitments to environmental sustainability, but practical barriers make it difficult to deliver on that commitment.
Pharma is Growing. Resource Requirements Need to Shrink.
As the drug industry continues to grow in size and volume, the industry’s emissions and resource usage are growing alongside it. Managing increasing energy consumption and environmental pollution at scale are no longer simply business continuity issues, they have become existential challenges. At scale, improving process design efficiency has across-the-board implications – potentially lowering waste and effluent production, energy requirements, water usage, resource extraction and more. Selectively employing single-use systems, for example, can make sense – depending on batch sizes and end-target product volumes.
Neuland Labs is proud to be a part of the journey discovering the right balance of measures the drug manufacturing industry can take.
Emphasizing Sustainability at Neuland Labs
Sustainability and environmental health and safety have been a focus at Neuland for years, but recently our commitment to sustainability was formalized among senior leadership as a guiding principle for our strategic priorities.
Communication with stakeholders has been – and will continue to be – critical to our efforts, spanning investors, board members, workers, clients, suppliers, the community and regulators.
According to Dr. Davuluri Rama Mohan Rao, Executive Chairman of Neuland Labs:
“By obtaining insights from 125 of our stakeholders across different sectors, we identified six key themes of sustainability: environmental stewardship, sustainable supply chain, employee nurturing, upholding human rights and ethics, economic value creation, and customer centricity. We used these goals to create a framework for sustainability at Neuland.”
Below we explore four of those areas in-depth.
1. Environmental Stewardship
While sustainability emphasizes the need for environmentally responsible products and services, the means to achieve it are often industry- or scale-dependent. A manufacturer, for instance, may have a very different read on sustainable practices than a consultant.
For us, minimizing the impact of manufacturing processes on environmental resources and further preserving them is a key priority. Our aim is to achieve zero landfill waste and become water-positive and carbon neutral by 2030.
Although the pandemic created some hurdles in the development of environmental protection infrastructure and improvement activities, we created a five-fold lower environmental impact in FY 21–22 over FY 20–21. To address greenhouse gas emissions and climate change, we initiated a low carbon pathway plan. Our carbon usage has gone down by 15% after a switch from double- to single-product washing cycles.
We also created a water management strategy focused on lowering water requirements and increasing the use of recycled water in our operations. All of our sites have adopted a “Zero Wastewater Discharge” policy, and we have two-stage high-pressure reverse osmosis systems that recycle 92–94% of our treated wastewater.
One area of focus for us is improving material efficiency. We’ve seen a 50% reduction in heptane and ethyl acetate use in ezetimibe manufacturing.
We are committed to the “wealth from waste” principle. One key target for us has been to achieve “zero land fill” for FY 23. As of August 2022, 100% of our total waste was being sent for recycling and co-processing in the cement industry.
2. Creating Sustainable Supply Chains
Last month, we explored supply chain sustainability and how our supplier assessment matrix includes not only delivery and quality metrics but also environmental and social measurements.
Pharma manufacturing requires key starting materials, intermediates, and specialty materials. The suppliers of these are the focus of Neuland’s sustainable supply chain efforts. Our supply chain team is trained in sustainable procurement practices and plays a key role in our development of domestic supply chains and a diversified vendor base. Our suppliers are required to adhere to a four-part code of conduct including human rights, ethical business practices, regulatory compliance, and safe operation conditions. The result has been geographical de-risking, a shortening of our supply chain, and an increased emphasis on ensuring our supply chain is diverse and inclusive.
3. Safeguarding Employee and Community Wellbeing
Employees are the heart of every company. At Neuland, we employ rigorous audit systems to safeguard employees from occupational injuries. Our team members undergo complete annual health check-ups and medical monitoring programs. To create a culture of sustainable business practices, personnel are trained on ethical compliance practices and behaviors to ensure we are adhering to regulatory policies and maintaining international quality standards.
As part of our broader focus on creating sustainable communities, we work to address community challenges through CSR initiatives targeting education, health, infrastructure development, and water availability.
4. Enabling Customer Interaction & Protecting Their Interests
Customers are a key component of the sustainability matrix. As a result, we seek customer input on specific ESG requirements.
A key aspect of protecting our customers involves the use of digital technologies. Such tools enable closer communication and interaction, improving real-time decision-making. Data-driven analysis allows us to create better, safer, more efficient and more sustainable manufacturing processes.
Our growing collective reliance on digital technology to improve our ability to drive value for customers also creates new risks. As an API manufacturer, we understand how crucial our customers’ and partners’ intellectual property rights are, as is the need to maintain strict confidentiality. Our strong digital cybersecurity and data privacy frameworks are designed based on the most relevant and highest-quality standards, and have eliminated any instances of identified leaks, thefts, or losses of customer data as well as security breaches.
Supply chain disruptions leading to drug shortages aren’t a new challenge. In fact, the FDA maintains a database of current shortages. But the problem appears to have become more pervasive over the last few years.
According to the World Economic Forum, multiple nations around the world are experiencing essential drug shortages. A survey conducted by the Pharmaceutical Group of the European Union noted medicine shortages in the 29 EU-member countries from mid-November 2022 through December 2022. Interestingly, 76% reported shortages that were worse than those experienced in 2021.
European nations are not alone. Hospitals in the US lack adequate supplies of liquid ibuprofen. Other drugs in high demand but short supply include Tamiflu, Amoxicillin, and Adderall. In Argentina, supply chain issues have inflated the cost of cancer medications by more than 50%, while Panama currently has the most expensive drug costs in Latin America.
All these issues are the direct result of breakdowns in pharmaceutical supply chains.
Effective supply chain management depends heavily on information- and data sharing up and down the entirety of the supply chain. Supply chain breakdowns, as seen during the pandemic, typically result from a lack of forethought, collaboration, or management in place to remedy the supply chain deficit. The impacts felt over the last several years have resulted in a tremendous shift in supply chain management approaches, with an emphasis on supply continuity.
As we’ve all now experienced, when supply chain management (SCM) is ineffective, the results are quickly felt by consumers…and have serious repercussions. Wallace J. Hopp, a University of Michigan professor, explains:
“Disruptions in medical product supply chains have greater implications than making people wait for a new television set. They have the potential to seriously compromise patient care.”
Managing the Links of the Pharmaceutical Supply Chain
Pharmaceutical supply chains include a sophisticated network of partners— suppliers, manufacturers, storage facilities, and distributors—all working to supply, produce, deliver, and sell quality drug products. These global systems involve numerous processes, individuals, policies and technologies, and their effective management is indispensable to the success of the pharmaceutical industry.
Mitigating supply chain risk demands continual vigilance in which every component and stage of the process is scrutinized and strategized.
It is not enough to merely identify risk. Companies must address potential issues with prompt and calculated actions and remain constantly alert to supplier issues.
Logistics challenges have been magnified by increasingly complex drug products. For example, many compounds – including those associated with mRNA vaccines – require refrigeration. The resulting cold chain logistics necessary to maintain product integrity have led to an increase in the risk of nonconformity.
Thankfully, Neuland’s commercial cold chain shipments have suffered no temperature outages, and every product for which we are responsible has remained in conformance. Our cold chain logistics success is directly attributed to having built reliable collaborations.
Maintaining Supply Chain Quality and Timeliness
The last few years have been a challenge for companies operating on a global scale. We’re proud of our successes despite the broader, global impacts felt across supply chains. Robust planning, strong communications, and a “proactive preparedness” approach have proven critical to consistent, secure product supply.
Here are eight aspects of supply chain management that we have found ensure product quality and availability are never sacrificed.
1. Risk Management
The proper management of risk helps control future outcomes through the proactive identification of risk factors, the determination of a risk’s impact, and the development of risk mitigation and prevention strategies.
For example, we have a dedicated Enterprise Risk Management (ERM) team at Neuland. This group of experts employs agility and foresight to ensure prompt and adequate responses to unforeseen risks. The team keeps a finger on the pulse of rapidly evolving demand patterns and consumer behaviors. They readily anticipate the need to reconfigure current strategies, processes, structure, personnel, or technology.
Rather than wait until a problem occurs, we proactively review potential scenarios and develop strategic answers in case a scenario materializes. The ERM team ensures viable options are already in place when unforeseen events arise.
The agility of this group was particularly evident during the COVID-19 pandemic. Neuland was able to navigate the challenges with minimal impact on our operations. Our effective risk management has been a testament to our reliability as a business partner and has made us a preferred choice for customers attempting to navigate the unpredictable global environment.
2. Vendor Depth and Selection
A ready pool of qualified vendors is necessary to ensure that there are sufficient suppliers. If a supplier is unavailable or becomes unsuitable, an approved backup should already be in place. The security of the supply chain is jeopardized any time an essential supplier vacates its position in the chain or performs at a subpar level. Proper manufacturer selection can result in:
Upstream processes significantly impact downstream processes. With raw material suppliers, for example, we use an active collaboration approach. We involve suppliers early in the development process, identify and strengthen areas of improvement prior to commercial supplies, and set clear expectations on specs, methods, governance and sustainability. This also includes multiple shipment tracking re-opening schedules, and closely monitoring outstanding receivables.
Pharma companies should always work with active pharmaceutical ingredient (API) contract manufacturers that are familiar with regulatory starting materials (RSMs), understand the chemistry, and have well-established sourcing procedures in place.
3. Logistics Improvements
As discussed above, logistics challenges have increased due to the growing complexity of drug compounds. Drug sponsors should be aware of the logistics dependencies their compound demands, and what potential impacts could occur as a result.For example, Neuland has secured new partnerships with GDP-certified logistics organizations. These new collaborations have expanded our ability to meet the needs of our customers without jeopardizing the quality standards.
4. Database Searches
When looking to enhance supplier management, a thorough and consistent review of high-quality certified databases, such as Directory of World Chemical Producers (IVQIA) and Row2Technologies, is essential. A deep search and a due diligence can unearth new sourcing options for specific APIs and their intermediates. Search results can be lackluster, however, if NCEs are involved and commercial RSM options are limited. When options are restricted, a research and development team may be called upon to develop a cost-efficient manufacturing process that can facilitate manufacturing through an external source.
5. Embracing Technology to Improve Operations & Supple Chain Visibility
Embracing industry advancements is crucial for any pharmaceutical company who wants to remain flexible, reduce costs and maximize supply chain visibility. Advancements in flow chemistry and enzymatic chemistry which improve yields and process efficiency are examples of technology impacting operations – and ultimately supply chains. At Neuland, for instance, we’ve found they can shorten processing times, increase production capacities, increase purities, and more.
Another aspect of technology – the digitization of our supply chains – data analytics, AI and automation are being leveraged to improve process efficiency and precision. Data-driven insights are helping to lower costs, improve forecasts and prioritize consumer health. Having real-time supply chain data is a must. It brings new levels of understanding to mixed-level details and material capacities, which in turn helps optimize production.
6. Inventory Management
Inventory management can be a trade-off, exchanging market service for servicing costs. Operationally, unavailability results in longer cycles, expiry-related issues, and regulatory requirements that reduce flexibility from inventory management. This is a double threat for generic drugs that straddle global markets, combining the regulated with the less regulated. Additionally, demand patterns have evolved with the pandemic, becoming more erratic. This has further accentuated the complexity of pharmaceutical supply chains. The risk of stock accumulation is also an important consideration. Some stocks should be increased at various localities given the risk of supply chain disruption from unforeseen events, while others should not.
7. Supply Chain Sustainability
Sustainable supply chains should remain a priority in your de-risking strategies. As an illustration, we have enhanced our supplier assessment matrix and added items that help lower supply chain risk. The assessment covers 80% of essential suppliers and 40% of all procurement. However, by 2025, we plan to cover 100% of suppliers in the sustainable supplier assessment plan. Our Supplier Sustainability Assessment Matrix includes the following assessments:
Due to our commitment to sustainability, we were awarded the prestigious Silver Sustainability Rating by Eco Vadis. Although we have made great strides, we continue our quest for all-inclusive, sustainable growth in the pharmaceutical industry.
8. Proactive Readiness
We’ve all learned that supply chain issues can arise unexpectedly and should be addressed promptly. We’ve found it best to take a proactive approach based on risk analysis. For example, Neuland maintains full visibility throughout the supply chain, allowing us to anticipate and avoid possible pitfalls.Being proactive helped us avoid prospective supply chain interruptions at the height of the pandemic. By increasing the inventory of key precursors that were critical to the functionality of our suppliers, we were able to repeatedly circumvent potential shortages and mitigate costs.
Interested in learning more about how Neuland leverages strong supply chain management practices to keep your drug API project on track and secure? Let’s chat – contact us today!
Just as COVID was making itself known in February 2020, the FDA was approving Esperion Therapeutics’ new first-in-class medication for the treatment of adults with heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease who require additional lowering of LDL-C.
The emerging coronavirus and the FDA approval would converge as Esperion planned on expanding Bempedoic Acid supply at Neuland in 2020, setting up a challenging manufacturing environment for this potentially ground-breaking drug.
Esperion Therapeutics’ NEXLETOL® & NEXLIZET®
Esperion Therapeutics began working with Neuland Labs prior to the pandemic to support expansion of Bempedoic Acid, the major active ingredient in NEXLETOL® and NEXLIZET®. In 2019, we entered into a technology transfer and supply agreement for the subsequent commercial API production of Esperion’s New Chemical Entity (NCE), bempedoic acid.
Overcoming a Challenging Pandemic Manufacturing Environment
The Esperion project encompassed technology transfer, pilot batch production, scale-up studies, process validation and production of commercial quantities of the Bempedoic acid API.
Neuland and Esperion worked together to put supporting processes in place. This ensured Esperion’s Process, Analytical, Engineering and Supply Chain teams possessed remote monitoring capabilities and could provide virtual guidance in real-time.
Developing and implementing this level of communication and access proved critical to every facet of the project, from technology transfer and production of pilot batches, to process validation (PPQ), global regulatory filings and – ultimately – commercial production. All documentation was reviewed and approved online by Esperion. The intercompany team reviewed the project twice weekly, with technical meetings focusing on scale-up of both the intermediate as well as bempedoic acid API.
Managing Through an Operational Slowdown
In terms of manpower management, lockdowns and strict safety protocols meant that our staff strength was, by necessity, reduced to 50% of pre-pandemic levels. To account for these manpower constraints, we prioritized the team working on Esperion’s bempedoic acid.
Facility and equipment readiness during the lockdown also posed additional challenges. Systems which were idled for extended periods needed to be prepared and brought back online.
Managing Difficult Supply Chains
COVID caused a slow-moving (and still – to some degree – ongoing) supply chain challenge. As the pandemic progressed through early- and mid-2020, two supply chain complications became all-too-common: uncertainty and interruptions.
While unsurprisingly, supply chain logistics did cause challenges in import/export, shipping of reference standards, impurity standards and samples, they were generally minimized.
We had already taken steps to ensure alternative supplier readiness in the event of supply chain delays or disruptions. In this particular case, however, the client’s vendors were already qualified. This meant that the project could rapidly shift to validation and commercialization work.
Outcome: Project Success
Our team was tasked with implementing the process outlined during technology transfer. The process and specifications were therefore in-line with the expectations set by Esperion. Consistent and regular remote collaborative work with the various in-house teams at Esperion allowed us to complete technology transfer, process validation and approval of Neuland in the global regulatory filings on-time.
We’re proud to say that the story does not end there. After successful scale-up, commercial production of the bempedoic acid was shifted from Neuland’s R&D Centre to one of the manufacturing units in Hyderabad, India for continued commercial production of global supply.
In late 2022, Esperion announced that their Cholesterol Lowering via Bempedoic acid, an ACL-Inhibiting Regimen (CLEAR) Outcomes trial met its primary endpoint, demonstrating statistically significant risk reduction in MACE-4 in patients treated with 180 mg/day NEXLETOL® compared to placebo.
Neuland is honoured to play a critical role with Esperion, providing prescribers innovative options to reduce LDL-cholesterol and overall potential cardiovascular risk for patients.
We continue investing in agile development and manufacturing capabilities to quickly respond to our customer’s needs. With the experience of working with Esperion, we have been able to successfully place processes to manage projects effectively minimising the need for on-site or in-person interactions.
While the pandemic may be behind us, we are seeing an increasing need for a CDMO to be self-reliant and self-driven to execute API expansion projects. In that context, working with Esperion has been a highly enriching experience for Neuland.