In pharmaceutical development, the race to bring medicines to patients faster—without compromising on quality—is more critical than ever. At TAPI, we’re answering that challenge head-on with an innovative platform that transforms how solid forms are identified and developed. By integrating computational tools with high-throughput laboratory automation, we’re not just streamlining solid-state R&D—we’re reshaping it. 

Rethinking Polymorph Screening 

Solid form matters. Polymorphs, hydrates, solvates, and amorphous structures may influence a drug’s solubility, stability, manufacturability, and regulatory path. Traditionally, uncovering these forms has relied on labor-intensive, trial-and-error methods. Our bespoke platform reimagines this process by combining computational tools modeling with smart experimental design. 

We leverage tools like Crystal Structure Prediction (CSP), lattice energy ranking, and targeted screening algorithms to identify different solid forms. Our unique approach allows us to creatively design the experimental plan before we even step into the lab—saving time, materials, and energy. 

From Prediction to Precision: Smart Experimentation in Action 

Our software-based systems are fully integrated with  automated high-throughput polymorph screening (HTPS). This means that parallel experimentation with multiple crystallization conditions can be conducted faster and more systematically than ever before. Using tools like PXRD, DSC, TGA, and microscopy, we can rapidly identify and characterize different solid forms with scientific rigor. 

And thanks to a closed-loop feedback system, experimental data feeds back into the AI models—making them smarter over time and improving accuracy with every iteration. 

Impact That Scales 

This is more than a lab breakthrough—it’s a platform with real-world impact. By enabling earlier identification of optimal solid forms, we help pharmaceutical partners minimize late-stage surprises, improve formulation robustness, and accelerate regulatory submission. It’s a smarter, safer, and faster way to advance drug development. 

A New Standard for Solid-State Innovation 

At TAPI, science is strength—and our innovative platform embodies our passion for advancing health from the core. By combining digital intelligence with expert intuition, we’re enabling our partners to make better decisions, faster. It’s not just innovation—it’s transformation. 

Whether you’re formulating a first-in-class therapy or optimizing a generic molecule, our AI-powered solid form platform is ready to support your journey. 

Let’s move beyond what’s expected. Let’s redefine what’s possible. 

At TAPI, we are dedicated to advancing sustainable pharmaceutical manufacturing by harnessing the power of cutting-edge science—particularly biocatalysis. One of our recent successes exemplifies this commitment: the development of a scalable, environmentally responsible biocatalytic process for the production of a complex chiral intermediate used in the synthesis of Avacopan. This achievement not only overcomes long-standing challenges in stereoselective synthesis; it also demonstrates the broader potential of enzyme-based technologies to streamline pharmaceutical production. 

By integrating biocatalysis into our development workflows, we offer innovative, greener alternatives to traditional chemical routes—delivering benefits in efficiency, selectivity, and sustainability. These capabilities are now a core part of our value proposition, both for our internal portfolio and for partners through our CDMO services. Whether optimizing existing processes or designing new synthetic pathways, we are helping to redefine what’s possible in pharmaceutical manufacturing through biocatalytic innovation. 

The Challenge: Double Stereocontrol with High Yield and Low Waste 

The synthesis of 2,3-disubstituted cyclic amines — especially with full control over two adjacent stereocenters — has historically been a significant challenge in API development. Traditional chemical synthesis routes for Avacopan’s (2R,3S)-2-arylpiperidine-3-carboxylate intermediate rely on diastereomeric crystallization, a process that discards nearly half of the material and yields only 42%. 

We saw an opportunity to develop a cleaner, more efficient alternative. Inspired by the principles of green chemistry, our team sought a stereoselective, biocatalytic solution that could reduce waste and improve scalability. 

The Solution: Enzyme-Catalyzed Amine-Imine Transformations 

Through extensive enzyme screening, we developed two innovative routes using imine reductases (IREDs): 

1. Oxidative kinetic resolution of the racemic amine, followed by catalytic hydrogenation for enantiomer recovery — successfully scaled up to kg scale. 

2. Dynamic kinetic reduction using enantiocomplementary IREDs — demonstrated at lab scale, showing strong potential for further development.

These pathways hinge on the reversible imine-enamine tautomeric equilibrium, which allows for efficient recycling of undesired stereoisomers and high selectivity toward the desired (2R,3S)-configured intermediate. 

Key Innovations 

• Enzyme Selection and Cofactor Regeneration 

We identified four commercial IREDs capable of enantioselective oxidation and two others for dynamic kinetic reduction. However, to make the process robust and scalable, we also needed an efficient system for cofactor regeneration. 

Traditionally, NADPH oxidases (NOx) were used for this role but posed challenges due to their sensitivity to solvents. Our breakthrough came with the application of alcohol dehydrogenase (ADH) enzymes — specifically from Lactobacillus brevis — as a more stable and scalable alternative for cofactor regeneration. This was the first reported use of ADHs in IRED-catalyzed oxidations, marking a significant step forward in biocatalysis. 

• High Selectivity and Improved Yields

Our enzymatic process achieved exceptional selectivity: 

• Oxidative route: >99.5% ee and >99.9% de 

• Reductive route: 98.3% ee and >99.9% de 

The oxidative route also significantly improved overall yield. By coupling it with a catalytic hydrogenation recovery step, we reached 72% yield across cycles — a dramatic improvement over the 42% achieved by conventional crystallization. 

• Scalable, Safe, and Sustainable 

Safety and scalability were paramount. Unlike earlier methods using monoamine oxidases and hazardous reducing agents (like boranes), our enzymatic routes avoid incompatible chemicals. The oxidation process was safely scaled to kg levels, with a high space-time yield of 37.2 g/L/day — a strong metric for industrial viability. 

In terms of sustainability, the use of biodegradable enzymes, mild conditions, and minimized waste supports our commitment to environmentally responsible API production. 

A Model for Future Development 

Our biocatalytic model provides a practical framework for innovation in pharmaceutical manufacturing, tackling issues that rise from a standard chemical synthesis approach: 

• It illustrates how the stereo controlled synthesis of complex amines can be achieved efficiently using green chemistry, addressing a long-standing synthetic challenge. 

• It expands the perceived role of ADHs by demonstrating their effectiveness in oxidation reactions, opening new avenues within biocatalysis. 

• It highlights how enzyme-driven processes can achieve both economic scalability and environmental responsibility—two critical priorities for the industry. 

Partnering for Innovation: CDMO Services at TAPI 

This breakthrough in the synthesis of Avacopan API exemplifies how targeted innovation, grounded in green chemistry principles, can transform pharmaceutical manufacturing. With better yields, reduced environmental impact, and strong scalability, this process is not just a milestone for TAPI — it’s a glimpse into the future of sustainable use of biocatalysis in pharmaceutical manufacturing. 
 
This achievement reflects more than scientific innovation—it demonstrates what’s possible when advanced technologies meet end-to-end CDMO support. At TAPI, we offer integrated CDMO services across every stage of development, from route scouting and process design to scale-up, GMP production, and commercial supply.  

Our global network spans 13 manufacturing sites and 5 R&D centers, supported by ~450 scientists and a deep toolbox of enabling technologies—from biocatalysis and flow chemistry to particle engineering and ultrafiltration. Whether your program involves small molecules, peptides, oligonucleotides, fermentation products, or HPAPIs, we’re ready to tailor solutions that accelerate your success. 

At TAPI, innovation drives everything we do—from early development to commercial scale. Crystallization is one of the most critical steps in API manufacturing, and gaining control over this process is key to achieving consistent critical quality attributes (CQAs), such as polymorphic form and particle size distribution. 

Traditionally, crystallization monitoring has depended on offline sampling, a time-consuming and complex approach that limits real-time insights and hinders process optimization. To overcome this, our R&D team implemented in-line process analytical technology (PAT) tools to solve a specific and scientifically challenging crystallization issue during the development of a novel API sulfonate salt. 

The challenge? A late-appearing polymorphic form—an industry-recognized risk with major implications for product consistency and performance.  

Leveraging Blaze high dynamic range (HDR) process microscopy in tandem with Raman spectroscopy, our scientists achieved rapid root-cause identification and developed a robust new crystallization process—demonstrating the power of real-time PAT integration. 

From Insight to Impact: Background & Approach 

During the first kilo-lab scale-up of the sulfonate salt, a new polymorphic form unexpectedly emerged—despite extensive prior screening. To tackle this, our team deployed advanced PAT tools, including HDR microscopy and Raman spectroscopy, for in situ monitoring of particle statistics and polymorphic transitions. 

This data-driven approach allowed rapid, informed decision-making and accelerated the development of a new crystallization process. 

Why PAT Makes the Difference 

The Blaze 900 system integrates HDR microscopic imaging, turbidity measurement, and Raman spectroscopy into a single, multi-functional probe. Its advanced image analysis algorithm provides accurate particle statistics—significantly outperforming conventional tools like PVM and FBRM. 

This capability enables real-time tracking of key crystallization phenomena, including nucleation, growth, attrition, oiling out, and polymorphic transformations—driving deeper process understanding and control. 

Overcoming the Polymorphism Challenge 

Lab investigations revealed that the anhydrous form of the compound could rapidly convert into either a monohydrate or a newly discovered methanolate, depending on the solvent system. These two novel forms, each with distinct crystal habits and thermal behaviors, were shown to be in an enantiotropic relation. 

With direct crystallization of the anhydrous form no longer feasible, our team pivoted to explore seeded cooling crystallization to obtain the monohydrate.  

This was followed by extensive Raman-supported solvent screening to enable a solvent-mediated polymorphic transformation into the desired anhydrous form—unlocking valuable insight into conversion kinetics. 

A Smarter, Faster Path to Process Development 

The integration of HDR microscopy and Raman spectroscopy enabled precise identification of transition points and streamlined the development of a robust crystallization pathway. This not only reduced development time but also improved product quality and ensured more reliable process control—highlighting the strategic value of in-line PAT. 

The combination of Blaze 900 in-line process microscopy with Raman spectroscopy marks a significant step forward in crystallization process development. By enabling real-time, in-depth process insight, these tools reduce reliance on offline analytics, accelerate development, and strengthen product robustness. 

At TAPI, we continuously invest in advanced technologies to drive smarter, faster, and more reliable API development—empowering our partners with solutions that deliver measurable impact. 

We’re proud to share our recent peer-reviewed scientific article, published in the prestigious ACS Organic Process Research & Development journal, titled “Imine Reductase-Catalyzed Synthesis of a Key Intermediate of Avacopan: Enzymatic Oxidative Kinetic Resolution with Ex Situ Recovery and Dynamic Kinetic Reduction Strategies toward 2,3-Disubstituted Piperidine.”

This milestone underscores the strength and innovation of our R&D team and marks TAPI’s presence in the global scientific community as a thought leader in process chemistry.

In this article, our scientists demonstrate the ability of proprietary imine reductases (IREDs) to control the configuration of two vicinal stereogenic centers in avacopan API via oxidative kinetic resolution. The system involves selective oxidation and tautomerization of the undesired enantiomer into a corresponding enamine. This byproduct is then either recycled via catalytic hydrogenation back to the racemic starting material or transformed through a dynamic kinetic resolution using another proprietary IRED with excellent diastereoselectivity. 

The process was successfully scaled to the kilogram level, with outstanding selectivity and yield. It’s an excellent example of how TAPI combines biocatalysis and process innovation to deliver efficient, sustainable solutions to complex synthetic challenges. 

Access the full article here.

At TAPI, our Contract Development and Manufacturing Organization (CDMO) capabilities are designed to address the complex challenges of developing oligonucleotide APIs. These advanced modalities require specialized expertise to ensure quality, regulatory compliance, and process efficiency from early-stage development to full-scale production. Our proven track record in overcoming technical challenges enables us to provide high-quality, flexible solutions tailored to our customers’ needs. 

A prime example of our expertise in action is our work on Nusinersen, a complex oligonucleotide API. Our recent discussions at TIDES Europe highlighted the intricate challenges of achieving regulatory compliance while maintaining the highest standards of quality and efficiency.

Expertise in Oligonucleotide Development: The Nusinersen Case Study 

TAPI’s experience in oligonucleotide development was demonstrated at TIDES Europe, where our R&D team presented critical insights: 

• Michael Tikhonov, R&D Analytical Group Manager, discussed the analytical challenges of developing generic oligonucleotides, particularly in impurity profiling. 
• Daniel Pinchuk, Group Leader Chemical R&D, gave an in-depth presentation on the development of Nusinersen API, emphasizing how TAPI ensures quality and regulatory sameness with the Reference Listed Drug (RLD). 

Daniel and Michael’s talk explored key factors such as phosphorothioates diastereomeric composition, and cost considerations, while also showcasing the advanced statistical tools TAPI employs to ensure similarity. 

Watch the Full Presentation: here 

Challenges of Generic Oligonucleotide Drug Substance Development

Developing a generic version of Nusinersen presents unique challenges due to its complex structure. In 2022, the FDA issued product-specific guidance recommending that generic versions establish diastereomeric composition sameness with the RLD. This is no small feat—Nusinersen is a mixture of approximately 130,000 stereoisomers! 

At TAPI, we take a rigorous approach to ensuring quality and sameness, from manufacturing process development to analytical characterization. Our methodologies focus on key parameters that influence the final diastereomeric ratio, ensuring regulatory compliance while maintaining high-quality standards. 

FDA Recommendations for Diastereomeric API Sameness 

The FDA guidance outlines several key recommendations for achieving sameness:  

• Selecting and controlling reagents and reaction conditions carefully  
• Measuring the R/S ratio at each elongation cycle using appropriate methods  
• Comparing the diastereomeric composition of the generic API to the RLD 

TAPI’s Approach 

At TAPI, we leverage advanced analytical techniques to ensure diastereomeric consistency in our generic Nusinersen API. Our approach includes: 

✔️ Evaluating the R/S ratio at each elongation step using LC-MS 

✔️ Carefully selecting fractions during purification to optimize the diastereomeric ratio and impurity profile 

✔️ Using ³¹P NMR fingerprinting, combined with PCA, correlation algorithms, and R/S ratio analysis, to demonstrate diastereomeric sameness 

By combining cutting-edge analytical tools with our expertise in complex API development, we ensure that our generic oligonucleotide APIs meet the highest standards of quality and regulatory expectations. 

CDMO Capabilities in Action: What This Means for Our Partners 

The challenges of developing Nusinersen illustrate the depth of TAPI’s CDMO expertise and our ability to tackle complex problems to deliver high-quality solutions for our selected partners. Our expertise will be at your disposal to: 

• Overcome complexity: Navigating the challenges of large stereoisomeric mixtures and ensuring regulatory compliance. 
• Innovate solutions: Implementing analytical and manufacturing techniques that enhance process control and optimize outcomes. 
• Ensure regulatory success: Adhering to FDA and EMA guidelines to guarantee product safety and efficacy. 
• Control isomer ratios and process stability: Managing chiral purity through purification, scale-up, and stringent process monitoring. 
• Optimize manufacturing from development to commercial production: Understanding process parameters that influence quality, ensuring smooth scalability, and implementing state of the art equipment. 
• Improve efficiency and quality: Process Analytical Technology (PAT) is implemented. PAT enables real-time, quality-based adjustments to the process. 

By leveraging these capabilities, we provide our partners with confidence in their oligonucleotide projects, ensuring a seamless path from development to commercialization. 

Customized CDMO Solutions at TAPI 

At TAPI, we offer tailored CDMO solutions for every stage of your API journey. With over 85 years of API development and manufacturing expertise, we provide flexibility and innovation to meet your unique needs. Our global presence, advanced technologies, and unwavering commitment to quality and compliance enable us to deliver solutions across a wide range of modalities. 

Our extensive experience spans advanced oligonucleotide modalities such as Antisense Oligonucleotides (ASO), small interfering RNA (siRNA), and Conjugated-Oligonucleotides. This breadth of expertise further reinforces our position as a leader in the oligo CDMO space, ensuring that we meet the evolving needs of our partners. 

Whether your project involves peptides, oligonucleotides, fermentation products, steroids, or small molecules, we are equipped to support you every step of the way. 

• Peptides & Oligonucleotides: Tailored manufacturing from research to commercial production, with reactor sizes ranging from 100 L to 2,000 L for peptides. 
• Wide Range of Capabilities: Offering regulatory starting materials, intermediates, and APIs for a diverse set of products. 

Whatever your project needs, TAPI is ready to deliver. 

Going the Extra Mile for a Greener and Safer R&D 

The TAPI R&D team developed an innovative ozonolysis in flow synthesis process that offers a selective and environmentally friendly solution to a challenging, synthetic step in our route of synthesis. A prototype of an in-house developed flow ozonator was created and subsequently applied to the design of reaction equipment, enabling larger scale synthesis.  

In this blog, you’ll see how this approach resulted in minimizing the environmental impact, improving product quality, and ensuring high process safety.    

 

Background    

The oxidative C=C bond has been identified as a critical chemical transformation in the manufacturing process of the API Voclosporin. Traditionally, heavy metal-based catalysts are employed for this type of reaction. However, these catalysts often lead to over-oxidation and impurity formation.   

The use of heavy metals presents several challenges in terms of:   

• Product contamination, as heavy metals can contaminate the final product, affecting its purity.    
• Environmental impact, as catalyst leakage into the environment poses risks to ecosystems.    
• Waste disposal and recycling, as proper disposal of heavy metal-containing waste is complex and costly.   

  

The Advantage of Ozonolysis   

Although various oxidative reactions can be considered for this purpose, only a limited number of transformations are compatible with the sensitive molecular scaffold of Cyclosporine, requiring high selectivity and process robustness. One such reaction meeting these criteria is ozonolysis.   

Ozonolysis offers a selective and clean alternative to heavy-metal based oxidative double bond cleavage. In ozonolysis, side reactions and impurity formation are significantly suppressed, resulting in a conversion rate exceeding 99.9%. Moreover, using proper equipment design, any excess ozone is catalytically decomposed back into oxygen.   

 

The Ozonolysis Challenge  

However, ozonolysis has significant drawbacks from an environmental, health and safety (EHS) perspective. There is an inherent toxicity and potential explosion hazard associated with the ozone, especially when mixed with flammable solvents, so precautionary measures are critical during the process design.   

 Large-scale batch ozonolysis is considered too hazardous, prompting the exploration of an alternative flow approach.   

  

The Flow Ozonator   

We set about to build an industrial flow reactor for ozonolysis, starting with a simple prototype based on 3D printing technology. This conceptual shift of reactor design aims to enhance safety while maintaining the desired reaction selectivity, product quality and process robustness. It also represents a unique solution since flow ozonator systems are not commercially available and therefore need to be designed as tailor made systems.   

A prototype of the flow ozonator was developed in-house in our R&D department. The first proof-of-concept system was 3D printed to verify basic functionality and perform feasibility lab studies. 3D printing technology was also used to improve the design of a larger scale, nGMP prototype that allowed us to overcome several technological challenges.    

The final design was subsequently applied to the production equipment, which met all Atex requirements of a production environment.   

The industrial equipment enabled successful production of GMP validation batches and will enable sufficient capacity. Notably, this approach minimizes environmental impact, improves product quality, and ensures high process safety.    

Side reactions and impurity formation are significantly suppressed, resulting in a conversion rate exceeding 99.9%. Additionally, any excess ozone is catalytically decomposed back into oxygen, minimizing any EHS risk.   

9 Key features, functionalities, and unique properties of TAPI’s flow ozonator are as follows:   

• Ozone is produced and consumed in the same close reactor zone.   
• Excess ozone is continuously decomposed to oxygen in the same close reactor zone via an implemented catalytic ozone destructor.  
• Low amount of ozone at any point in the reaction – less than 100 mg.   
• High level of operator protection.    
• Low amount of flammable methanol actively mixed with ozone in the air – less than 50 mL.  
• Very short residence time – less than 10 s therefore overoxidation / formation of by-products suppressed.   
• Low reaction temperature used – reduced solvent vapour well below the flash point of methanol in air.   
• Very low accumulation of reactive intermediates.    
• Since synthetic process in production is continuous and there are no interruptions or delays, predicting and managing production times and costs becomes easier for businesses.   

The implementation of this creative in-house ozonolysis flow technology significantly enhances process safety, robustness and mitigates the environmental footprint associated with chemical processes and optimizes product purity profile and quality.   

It also represents a remarkable example of the benefit of continuous manufacturing applied to a challenging transformation of a complex API.   

For the avoidance of doubt, TAPI is not offering Voclosporin and will not sell Voclosporin, if such offer or sale infringes valid patents, unless in accordance with conditions permissible under applicable law. 

 

At Teva api R&D, we work extremely closely with our customers to develop drug substances that best fit their formulation needs.  

In generic API development, we identify the most likely formulation and focus on potential critical attributes in the API that may impact the formulation process and properties. When providing CDMO services, our focus is to develop APIs to make the formulation process development easier and increase probability of success in clinical trials.  

Our aim is to offer the customer APIs which will be the most suitable to formulate, based on dosage form. We offer:   

1. Several crystalline forms (when possible). 
2. Several API grades,tailored to accommodate customers’ needs 
3. An extensive API characterization package with special focus on formulation-relevant attributes, including PSD, particles morphology, SSA, BD, and TD. 

Once we gain an understanding of a customer’s potential dosage form and specific formulation, API attributes are tailored based on the identified needs of the pharma team, taking into account bioavailability and stability requirements, manufacturability, and IP limitations. Each route of administration, dosage form and formulation, has a specific focus regarding API development. 

 

Oral dosage forms 

An oral solid dosage form (OSD) includes tablets, suspensions and capsules. Tablets are the most common type of OSD, about one third of all prescriptions. In fact, sources estimate OSD to be approximately 65% of the market.  

Most oral drug products are categorized by the Biopharmaceutics Classification System, the BCS, as part of the innovator’s NDA filing.  

BCS is tool used for classifying orally administered medicines based on dissolution, aqueous solubility and intestinal permeability, which affect the absorption of active pharmaceutical ingredients (API).  

Our teams take the BCS classification into account when selecting the crystalline form of the API for development. Many molecules being approved have low solubility, or BCS class II or IV, so require special attention.  

Whether it is a crystalline anhydrous form, a solvate, or a salt, the API attributes are finetuned to match the formulator needs.  

Nowadays, more and more API products have low solubility, therefore require special attention from the formulator and from us. The crystallization process has paramount importance to define the crystalline form (or to afford amorphous API), but also to finetune particle size and morphology, in combination with the particle size reduction technique that may be applied.  

Another challenging case is when there is high loading of the API within the drug product, that in specific products might reach above 25% weight per volume (w/v) in a capsule. Extra care about API properties must be taken when developing for such high loading formulations.  

 API properties have a major impact on the formulation process and attributes of the drug product.  

Physical-chemical properties of an API, including flow ability, mechanical properties and chargeability, will all be taken into consideration by our teams through all stages of development, depending on the specific formulation.   

Bulk properties of API particles will be specially tailored to facilitate formulation development and to enable robust formulation process. 

 

APIs for inhalation products  
Another example of drugs strongly impacted by API characteristics are inhalation products. Since the final drug product is administered in a device, such as an inhaler, the quality of the API is often very low.  

Examples of this are dry powder inhalers or metered dose inhalers. Here, the API is formulated mainly with lactose or gas. API attributes are of special importance here since the number of components is very limited – just the API, usually one or two additional excipients and the device itself. Each component has a massive impact on the efficacy of the product, unlike other drugs where there is a lengthier list of excipients. 

The drug also needs to reach a specific place in the lung, which is dependent on particle size. If the size of the particle is too big, they will be deposited in the mouth or throat. If the API particle is too small, it will not readily sediment and could be exhaled.  

 As an API developer, we can leverage the ability to change morphology and PSD according to the customer’s choice of device. Critical attributes such as amorphous content and SSA will be carefully monitored in any particle size reduction treatment. 

Since the optimal physical characteristics of the API will depend on the device, all API properties must be tailored to the specific needs of the customer. This includes particle morphology, PSD, surface characterization, amorphous traces, flow ability, density, chargeability, and mechanical properties.  

  

Suspensions  

Lastly, suspensions are used in various administrations either for injections, for topical administration such as creams, or for oral administration. Each type of suspension needs special consideration as the formulation may be liquid or semisolid, oily, aqueous. 

Developing a suspension requires special attention to the surface properties of the API particles, which are in direct interaction with the continuous phase in formulation from which absorption takes place and therefore therapeutic effect.   

In all these cases the thermodynamic balance which will enable stable suspension formulation requires that surface properties of a crystalline or amorphous API, base salt or a co-crystal API will be custom-made and fully characterized. 

Nowadays, with CDMOs increasingly leading innovation for pharmaceutical partners, we are required to go the extra mile to speedily develop high-quality APIs and accommodate the specific needs of the customer. 

We therefore implement cutting edge computational modeling, automation and high-throughput screening (HTS) in our development. Customers can also rely on the support of the Teva api team to holistically support their specific needs either in generic or specialty drug product development. 

 For more information on our CDMO services or APIs, please reach out to our team.    

API sterilization is a very niche market. But when it’s needed, it must be done right. Sterilization a crucialis a crucial step in the manufacturing of certain drug products and is key to ensuring patient safety. 

Over the last few years, Teva API has been developing a state-of-the-art sterilization facility in Croatia that was built purely for this purpose. The site has recently started manufacturing two products with the potential for a much larger capacity. This facility is a unique and rare asset in the pharmaceutical market, complete with complex technologies that are not commonly seen. 

 

 

Background of the Facility: 

The project started from the ground up in 2016. Over a three-year period, the facility was designed and built, equipment was purchased, and the cleanroom and equipment installation was completed. From 2019 to 2022, the focus was on qualification activities, process simulation tests, and low volume manufacturing activities.  

In 2023, the site successfully received a manufacturing license, in line with all regulations including the recently updated Annex 1, allowing Teva API to begin to produce and distribute GMP material.  

The intention from the outset was to cover TEVAs own API’s as well as offering our services to third parties (CDMO).  

 

The Facility: 

The sterilization line is fully automated and operated in a completely closed environment where everything is controlled — from equipment to material. This is to ensure that no foreign particle or biological contaminant is introduced into the process and end material. 

Regulation is obviously one of our top concerns. The facility has an excellent regulatory record, with stringent quality and safety considerations incorporated throughout every aspect of the process, in close coordination with national and international health authorities.  

 

The construction material used in the facility is Hastelloy, rather than standard stainless steel. This allows for more flexibility in selecting the process, solvents, APIs and PH as Hastelloy is a much more endurable stainless steel.  

Another important element is that we have validated the plant to operate with OHC level 4. This means we can meet the requirements of the environment outside the isolator, which allows us to have maximum 1-10 micrograms of the API inside the cleanroom.  

The first out of two sterilizations line can deliver batches ranging in size from 5-35kg.   

 

The aseptic filtration process 

There are several different methods which can be used to sterilize APIs — such as dry heat, moist heat, and Gamma irradiation. At Teva api, we offer the noninvasive high-performance aseptic filtration. With this method, the API is not damaged, and no new impurities are formed. 

First, the API is dissolved. The solution is then filtered through a 0,22 micron membrane, which removes all biological contaminations. The API is then crystalized, dried, and micronized according to the particle size distribution (PSD) level requested by the customer. We can accommodate a wide range of PSD specs. 

Since the majority of sterile APIs we’ll be producing, will be used in their final form as suspensions, one of the key parameters is PSD, i.e. the size of the crystal. One of the first things we do with a potential customer is to evaluate the specification and see if we can fit the PSD request.  

Of course, we run a closed process. We use isolators throughout the entire process to ensure sterility and minimize the risk of contamination. It’s a grade A environment, of course, and the background of the isolators is a grade C.  

 

Packaging: 

Once the API is ready, there are two primary packaging solutions available for these sterilized products.  

The first is a multilayer 5-liter PE bag, and the second a 5-liter aluminum container that is stoppered and crimped. They both arrive to the site gamma irradiated and are then filled with the product and wrapped 4 times.  

To discuss our sterilization services further with a member of our team, please contact us. We’d love to hear what your needs are and see how best we can support you! 

 

The sale is prohibited except for the purpose of obtaining marketing authorizations, and is only permissible under and in accordance with applicable law.

 

 

 

This article was originally published on 12.11.2020 and has now been updated with new information.

Whether a dose form is a tablet, capsule, injection, suspension, or any another formulation, API’s physical properties play a key role in determining whether the finished dosage form will perform effectively. 

Particle size distribution, or PSD, is probably one of the most important physical properties of an API. Most of the time, it is a critical parameter that can affect your formulation process and bioequivalence.  

To meet the specifications, the API provider must possess expertise in crystallization and size reduction processes. At Teva api, our experience has taught us that it is essential to collaborate closely with pharmaceutical manufacturers to set the right specifications that suit the formulation needs. This collaboration will ensure the API is manufactured flawlessly and that there will be a consistent supply. 

The approach for setting PSD specifications is different from setting chemical specifications, in several ways: 

• Physical quality is a tailor-made property based on the drug product 

Specifications usually define an acceptable upper limit of a certain impurity (i.e., percentage of impurity, residual solvent, etc.). With particle sizing, limits on sizes are based on what impacts your formulation process or drug product profile. For instance, in some cases you may require exclusively fine particles or a more flowable powder with coarse particles, while in other cases, particle size will be a less important parameter. 

• Physical quality is related to your formulation process  

The limits will often be well defined in pharmacopoeias and official quality guidelines, guiding the definition of a specification limit that is accepted by many authorities and manufacturers. However, physical quality is client specific. Your formulation can be complex and sensitive to small changes in particle shape and size. For that reason, particle size specification can be specific for formulation process. 

• There are no universal methods for PSD measurements

Pharmacopoeias do not define universal methods for PSD measurements, and different methods such as sieving, or laser diffraction microscopy, will deliver different results. Even different instruments working on the same principle, such as different models of laser diffraction instruments, might deliver different results. In addition, each method is product-specific depending on various factors potential solubility and morphology. 

As a result, the API provider should adopt a case-by-case approach and work closely with the pharmaceutical manufacturer to ensure specific needs are met. 

Details are Essential 

As the particle size increases, its surface area decreases, resulting in a decline in the rate of dissolution over time. The dissolution curve may have a “tail” of longer dissolution times that is dominated by the last few coarse particles to dissolve.  

For that reason, it is necessary to control the content of both average and coarse particles. 

Besides affecting dissolution, particularly for poorly soluble APIs with low bioavailability, particle size can influence the behavior of the bulk powder while being stored or formulated.  

Presence of agglomerates and aggregates should be evaluated to make sure that the particle size method is fit for the purpose. Whether you need to monitor the size of the primary particles for better dissolution control or want to control the presence of agglomerated and aggregated particles, Teva api develops the materials and methods that are relevant to your product. 

Besides using laser diffraction measurements, we employ optical and scanning electron microscopy to learn more about the shapes and sizes of the particles. This allows us to better define the powder and our particle sizing methods.  

Particles are three-dimensional objects while particle size distribution gives only one dimension as a result, the diameter of an equivalent sphere. Thus, microscopy is an essential part of interpreting the results, especially for particle shapes that are far from spherical, for example needle-like, columnar, plate-like, or flake-like. We make sure that the results we obtain are representative of the powder. 

When it comes to the dosage form’s manufacturability, other properties are also important. Material needs to be free-flowing, non-sticky, and must easily blend with excipients.  

Dissolution occurs faster with fine particles while manufacturability is easier with coarser particles. A well-defined specification that balances these requirements is the key to production robustness. 

It is important to remember that the different estimators for PSD are not mutually exclusive. If the API is milled in order to reduce d(0.9), the d(0.5) will decrease as well. 

In addition to PSD, other physical properties that may play an important role in pharmaceutical manufacturing, will be specified as well such as Bulk Density and Tapped Density.

 

Statistics Rule! 

APIs are powders that contain a multitude of particles, each with a different size. The population of the particles is commonly called a statistical point estimator. For example, the term d(0.5) is the population’s median particle size and is a statistical point indicator. 

One of the most important concepts that applies to these terms is the central limit theorem. This fundamental statistical rule implies that statistical point estimators will always be distributed normally, regardless of the distribution of the population they describe.  

This concept can be easily illustrated by the following simple dice-throwing game: when a single die is thrown, the distribution is uniform. The chances of obtaining any value from one to six are equal. However, the arithmetic mean of many rounds with several dice will converge in a normal (Gaussian) distribution with a given average and standard deviation. 

So, although API manufacturing is a well-controlled process, the median PSD [d(0.5)] of many batches will always have a certain normal distribution with a given average and standard deviation. Tight control over the crystallization parameters and particle size reduction technique settings may reduce the standard deviation, but some variance will always be there. The same applies to d(0.9), d(0.1), etc. 

Therefore, a product specification is best defined when it is based on statistical data from many batches. Teva api scientists have developed a methodology to generate specifications with statistical significance based on a wide database of many commercial batches, as well as on a limited number of lab and pilot batches for new products under consideration. 

Trends in Regulatory Requirements

Today, most health authorities recognize that PSD and other bulk physical properties should be defined in specifications.  

The current trends include: 

• Requiring three-tiered specifications. For example, requiring limits on d(0.1), d(0.5) and d(0.9). 
• The limits may be one-sided or in some cases a bi-sided limit will be required. 
• Other physical properties should be defined if it been found to be a Critical Quality Attribute (CQA). For example, Bulk Density and Tapped Density. 

Wide or Narrow? 

The range of bi-sided specifications should be carefully selected. Ranges that are too wide may cause the final dosage form to fail in dissolution testing. Therefore, the limits should be selected with some safety margins that are evaluated during the development of the formulation and the biostudy. 

On the other hand, ranges that are too narrow compared to the normal distribution of the provider’s API batches may make it difficult to consistently manufacture material that complies with the specifications. 

 Examples for PSD Specifications Format 

• Three tiers: d(0.1), d(0.5), d(0.9) 
• Control of coarse particles: Upper limit for d(0.9): d(0.9) NMT XX μm. This limit will ensure dissolution. 
• Control of average particles: d(0.5): NMT XX μm  and/ or  NLT XXμm This limit will ensure consistency. 
• Control of fine particles: Limit the bottom range for d(0.1): d(0.1) NLTXX μm. This will ensure manufacturability. 
• Bulk and Tapped Density: Set a bottom limit for these values. 

Accurate PSD Specifications Begin with Reliable Data 

For commercial products, Teva api maintains a statistical database of physical properties from at least 10 batches on a commercial scale. In many cases additional data is available from multiple sites, historical trends, etc.  

This data is used to propose specifications and recommend analytical methods to customers. If the customer uses a different PSD method, both should work together to align results and specification limits. 

Creating specifications for a new product is more challenging because of the absence of a statistically significant database. Teva api uses statistical tools to forecast the future variance of production batches based on limited commercial data, with additional data from smaller-scale manufacturing.  

Over time, this process has been proven to provide accurate limits for specifications. As with commercial products, it is essential that the API provider and customer align their PSD analytical methods. 

It takes a strong working relationship between the API provider and finished drug product manufacturer to produce and deliver high quality APIs. Careful planning, open communication and close collaboration with a trusted partner will ensure that you receive a consistent supply of superior products – the key to your success in today’s marketplace. 

Thank you to Oshrat Frenkel, Dario Klaric & Marina Ratkaj, for their contributions to this article.