We recently held a webinar on the topic of changes and updates to global API regulation in 2023. Teva api regulatory experts from across 5 different markets – US, EU, LATAM, Japan & China, came together to talk about what’s new in each market, and to share their insights about what to be looking out for this year and beyond.

Here are the highlights from the webinar:

Rodrigo Silva focuses on Brazil and Mexico, explaining that the main hurdle for Mexico in terms of getting registered is surpassing the need for the local inspection. In Brazil, the new CADIFA regulations came into effect, full force, as off August 2023, and he talks about the support needed locally to successfully obtain CADIFA. Similar to Mexico, he also details what has changed regarding inspection reports.   

Ana Bohanek dives into US regulatory highlights, mainly the DMF relevant enhancements under GDUFA III, reauthorized in September 2022. She discusses changes to DMF solicited off-cycle amendments and the criteria for DMF review prior to ANDA submission.  

Tzofit Kehat then goes over the main changes expected in the European market. She outlines the pharma legislation revision published by the European Commission that focuses on a new centralized procedure, and then details the CEP of the (near) future.  

Jay Chen talks about what makes China’s emerging market unique in terms of regulation. She outlines the key trends and key products in China, and also what special requirements are needed there, such as how APIs are managed as medicines, and how only one supplier can be submitted with an ANDA. China also faces multiple challenges including different communication channels to elsewhere and how they’re going forward with digital promotion. 

Lastly, Marianna Kishinevsky discusses Japan and how Teva api helps customers navigate this challenging market, in terms of new submissions and their workflows and timelines, and the preparation and lifecycles of DMFs.   

We recently held a webinar on the topic of change management in Japan. Teva api regulatory and change management experts, Marianna Kishinevsky and Rinat Bordman, discussed the change management landscape in Japan and how we, at Teva api, utilize our local, dedicated team in Japan to navigate the complex and frequent changes that require control and review.  

Watch the short webinar here below!

Marianna and Rinat outlined Teva api’s operations in Japan and all the supporting functions that contribute the right expertise in regulatory and change management. They explained where the changes come from – whether internally from Teva api’s manufacturing sites or from the PMDA authorities. They went into detail about the different types of major and minor changes that can and do occur and what’s needed from the team from the initial pre-notification of the change all the way through to submission. With major changes, there’s obviously a potential risk to the supply, so a lot more is needed to manage and deal with the change. Teva api’s special internal taskforce brings in all the relevant people to effectively manage the implementation of the change.  

They gave real and current examples of changes that were recently implemented in Japan and explained why changes occur in general. Marianna explained that changes are usually driven by the product strategy – to do with quality of the materials, changes of the supplier, procurement changes, cost reduction and so on. It’s an active industry where changes are a normal and natural occurrence.   

Lastly, they went into detail about how Teva api builds a resilient supply chain for change management and what’s needed to ensure minimum impact to the customer, making sure there’s clear communication and that the customer has enough stock until the change is fully implemented. Rather than having any external dependencies, we ensure that everything is controlled internally so that changes are easier to manage.

We recently held a webinar on the topic of ‘Smart tracking of your APIs”. Teva api supply chain expert, Bertil Wagensveld, discussed the new GPS data logger that Teva api uses on cargo to give full transport visibility, all the way from when the shipment leaves our manufacturing site until it gets to your door!

Go on, it’s worth a short watch!

Bertil outlined the challenges encountered with conventual data loggers. He talked about an increase in temperate deviations due to global warming and certain global events. He explained how conventional data loggers give limited data since customers need to manually return this data to Teva api. He also talked about the overall increase of cold chain volumes and shipments globally and at Teva api, where significant temp deviations could direct the direct costs associated with them.

He then delved into the new revolutionary solution that Teva api are now spearheading. It uses real-time tracking that can be accessed by anyone in the chain – Teva api, other relevant service providers, and of course, the customer. It shows any deviations or weak points in the chain, which can then be dealt with immediately. He spoke about what was required to set up this new device and the benefits that all stakeholders are experiencing on a daily basis.

If you want to learn more, watch the full webinar below.

Our recent webinar, Sustainability by Design — Implementing Safe Solutions to Reduce Risks, was all about how the Teva api sustainability team ensures safe solutions are implemented from the earliest stages of API development all the way through to the commercial stage.

Speakers included Franjo Yovich, Principal Pilot Engineer at the PLIVA site in Croatia; Gaash Bar Tal, Director of Sustainable Operations and Green Technologies in Teva’s Global Manufacturing Tech Support Group; and Moshe Turgeman, Associate Director of Process Safety at Teva api.

The webinar covered multiple topics, including:

• What sustainability in the labs actually means
• How to identify highly-hazardous materials
• Why flow chemistry is a hot new technology
• How to judge if a product is safe or needs to be ‘let go’
• What equipment is needed to discover risky situations

Franjo spoke about the safety aspects of process development. He explained how to know whether our processes are safe or not, and what information we need to provide to our colleagues in production to keep things safe.

He showcased some recent terrible disasters in the news, where factory explosions caused many casualties in Slovenia, Bosnia and Lebanon, and described the equipment Teva api uses to detect unsafe processes.

Gaash explained what process sustainability is, why we need it, and how Teva api embeds it into the product lifecycle. He explained how sustainability is a combination of the economic aspects, environmental aspects and social aspects.

With pharma, which is such a resource-intensive industry, the API part is actually the biggest contributor to the sustainability of the pharmaceutical industry. We are producing 150kg of waste per 1kg of API we are producing, 90% of the total mass of API production is coming from solvents and water, and 80% of the environmental footprint of API production is related to solvent and energy management.

So focusing on process sustainability as part of the product lifecycle management in API production is crucial.

Moshe described how Teva api implements solutions to reduce risks. The answer is three-fold: safer material selection, better wastewater treatment, and safer work processes.

He talked about the standards and guidelines that Teva developed, as well as design principles as part of the engineering process. These were distributed across all Teva sites and employees were fully trained on how to reduce risks.

At the end, the speakers answered 3 questions from listeners.

1. 
   

   Do you have a system to evaluate product sustainability?

   
   

Gaash talked about the internal tool Teva api developed called the ‘eco-efficiency tool’ to evaluate product sustainability. In the evaluation, they score different aspects of the process, like temperature, yield, volume, solvent selection. Each aspect gets a score and the entire product gets an aggregated score of up to 100. The more sustainable, the higher the score. Once you have the score, you can analyze and act upon it and know exactly where your place your efforts in the lifecycle management.

2. 
   

   Is there a system that helps to exclude an unsafe process? Are all processes in Teva api safe?

   
   

Franjo answered that emphasis should be put onto the understanding, putting all the knowledge together and deliver it to production. Teva api adopted a system from scientist, Francis Shtesel in the late 2000s in which all processes are put into a criticality class based on temperatures. The ratio of different temperatures will tell us which kind of criticality class we have. Criticality class 1 means a safe process and we can go further and criticality class 5 means unsafe and needs to be reworked. Using this approach, we can determine what is safe and what is not.

3. 
   

   Could you provide an example of implementation of inherent safety in design with a passive element?

   
   

Moshe said that once we know the criticality of a reaction, we go through designing of an emergency relief system. For this, you need data from the early stages of development, and we also use external world acceptable software. We plug in all the elements of the chemical reactor, including volume, size and quantity, and then design the proper vent sizing in case of emergency. This way, we implement our development data into our engineering.

If you’d like any more information on sustainability, reach out here or watch the full webinar below.

Particle Size Distribution is one of the most important physical properties of powder APIs. To ensure robust formulation, it is essential that PSD measurement be accurate, repetitive and consistent. Teva api uses industry-leading best practices for PSD method development, such as microscopy and laser diffraction, to support more than 350 APIs and help us meet each customer’s unique needs and specifications.

What is Particle Size?

Particles come in many shapes and forms, some are easy to characterize and some are difficult, depending on the morphology and the shape of particle.

In order to measure the particle, we need to convert each particle into a sphere, theoretically. The sphere is equal to the particle it represents. By converting the particle into a sphere, we get one dimension with which to measure the particle – the diameter. The conversion itself is done by volume or mass or any other property, depending on what we want to measure.

This conversion into a sphere is relevant for a single particle.

Particle Size Distribution (PSD)

A bulk however, isn’t comprised of a single particle, but is a statistical population. It usually behaves in a normal distribution. When we measure the particle size, we don’t measure a single particle but the entire population. Doing this gives us the particle size distribution, PSD. The PSD is a statistical characteristic.

While we measure all the particles in the sample, to describe a distribution we usually note three percentiles: D90 – the larger particles in the sample, D50 – the medium-sized particles, and D10 – the small particles. Once we know the sizes, we know how to deal with the bulk.

Measuring Methods

Our results are as good as our methods. We need to consider two things when choosing our measuring technology. The first is how accurate the method is, and the second is how repeatable the results are using this method.

There are 3 main methods for analyzing particle size.

1. Laser diffraction – we use a device that lights a laser beam through a suspension of the sample. A detector senses the way the laser diffracts within the suspension and can therefore determine the size of the particles within the suspension. This method converts the particle to a sphere through volume. It is the most common method
2. Sifters – we measure the weight of the sample and how much weight is left on each sifter. This is a relatively old method but is straightforward and effective.
3. Image analysis – we take a small sample from our batch and take microscopic pictures of it and measure particles by hand, using measuring software.

Bulk and Tapped Density

Bulk and tapped density are two important properties to understand. Bulk density is the density of the powder at rest. There are some small particles, some large particles, and a lot of air between them. This gives us a certain amount of product per volume which is the bulk density.

Tapped density is what happens to the particle after you’ve tapped the sample. The small particles realign and fill the gaps between the large particles, which means the volume of the entire bulk reduce, which increases the density. We use a tapping device to do this.

Why Mill APIs

By controlling the particle size of the API we can control the dissolution profile and have the desired results for the final dosage form. This is extremely important.

Another thing we can control with the particle size is flowability and handling. Usually large particles tend to flow better and be less sticky than small particles. The one we want depends on what result we’re trying to achieve.

Another thing to consider is compatibility with the formulation. Particle size differs for different formulations, such as tablets, capsules or inhalation products.

Lastly, we need to make sure the API is a smooth flowing powder without any aggregates. We mill them in order to achieve this consistency.

3 Top Milling Technologies

At Teva api, we use multiple types of milling technologies. The three most common ones are:

1. Cone Mill
   
   This is the least aggressive one. It is meant for large particles, ranging from 100-1000 microns. It’s a conical screen with a rotating impeller in the middle. Once the impellor is rotated, the particles are first impacted and then sheared by the screen.
2. F-10
   
   It’s made of two milling chambers. The first milling is done on the top and it’s very similar to the cone mill. The second chamber provides a secondary impact for the particles that breaks them into an even finer dust. This mill heats up so it has a cooling jacket so that the chemical properties won’t be affected by the heat.
3. Spiral Jet Mill (Micronizer)
   
   This uses only compressed air without any moving parts. A strong stream of jet using air or nitrogen pushes the particles into the micronizer chamber. The chamber is round so the particles move in a circular motion. The particles collide with one another and result in them breaking into fine dust. The fine particles leave the chamber through the middle, while the large ones stay in the chamber and can only “leave” once they’re small enough.

Webinar: The Perfect Particle – Why Size Matters

Interested in more resources on PSD? Our webinar, The Perfect Particle — Why Size Matters, was a deep-dive into the world of particle size. Particle size is one of the first physical properties that needs to be considered in an active pharmaceutical ingredient (API).

During the webinar, Zohar De-Valenca, our Senior Manager of Manufacturing Sciences & Technology, spoke to our listeners about why particle size is so crucial and what top technologies exist for the milling of APIs. Enrico Bettitini, Subject Matter Expert in Solid State, then answered questions from the audience.

If you’d like any more information on PSD, reach out here, or watch the complete webinar below.

Our recent webinar, Nitrosamines: A Moving Target was a deep-dive into the issue of Nitrosamines impurities and how you can stay on top of the various evaluation requirements to remain compliant.

During the webinar, Diana Van Geenhoven, our head of global compliance, Lena Ben Moha-Lerman, Senior Director of Lifecycle Management within Teva api’s R&D team and Vesna Prgomet, our Director Global Regulatory Affairs, spoke to our listeners about the critical three-step approach when it comes to Nitrosamines, Risk Assessment, Confirmatory Testing and Changes for Marketing Authorization.

If you missed the live event, here are your highlights!

What changes should I look out for when it comes to Nitrosamines?

Over the past three years, there have been a lot of changes in Nitrosamines regulations. While the evaluation requirements started out with a focus on NDMA, now the guidelines contain many other Nitrosamines, too. It started out with Valsartan as the main product to be included, and now all chemical synthesized medicinal products as well as products produced by fermentation and biological syntheses have to be assessed. Acceptable Intake levels also have been changed during the last years.

Other extensions to the regulations include regarding the root causes for the presence of Nitrsosamines for example checking for cross-contamination as part of your evaluation.

In some cases, the evaluation criteria actually has become less stringent. For example, back in 2019 the FDA said that Nitrosamines in Sartans should be undetectable. However, in 2020 – the FDA updated this with new guidance and relaxed this requirement. Timelines have also been changed, especially in response to the COVID-19 pandemic. For example, the EMA relaxed the deadline for the first step in the Nitrosamines assessment from March 2020 to September 2020 and then again to March 2021.

Lastly, several publications have been issued over the past three years which explain the different ways that you can test for Nitrosamines, depending on the product you’re testing.

Risk mapping for Nitrosamines

There are three steps for Nitrosamines’ risk mapping. The first is the theoretical risk assessment. If a risk is found, you then move to confirmatory testing. If indeed Nitrosamines have been found at a higher amount than the limit, you will need to optimize or change the process before submitting this change to the relevant regulatory agencies. Let’s look at each stage in more detail.

Risk assessment

Theoretical assessment should address all root causes as defined by relevant guidelines and can be grouped in three potential sources for risk with Nitrosamines. These are the chemical process, cross-contamination and contaminated raw materials/solvents.

Nitrosamines formation is attributed to a reaction between the secondary amine and nitrite ion, therefore Nitrosamines can be formed in chemical process only if both of these are present. If one of those components is missing there will be no risk of Nitrosamines formation.

It is important to emphasize that secondary amine doesn’t have to be present as it is, it could also be sourced from primary/tertiary/quaternary amine that is used in the process. Secondary amines can be also process intermediates of the API itself. Similarly, nitrite can be used itself in the process or it could come from other sources such as hydroxylamine or nitric acid. Process water should also be assessed for the presence of nitrite ions, as they can react with amines used in the process.

Remember: Secondary amine and nitrite ion don’t have to be used in the same synthetic step. Traces of reagents might be carried over to the later steps.

Another aspect of potential risk could be contaminated starting materials and solvents, such as recycled solvents or materials that we source from a third-party. To address this risk at Teva api, we send dedicated questionnaires to all our vendors and based on their answers we conclude whether or not there is a potential risk. In case we conclude that there is a risk – API produced from this vendor is subjected to confirmatory analysis.

Confirmatory testing

Confirmatory testing is required for commercial products as well as for any new products to be launched. Different regulators have varying amounts of Nitrosamines that are considered to be acceptable. For example, under the EMA guidelines, less than 10% of the Acceptable Intake is considered to be low enough risk, while the FDA doesn’t spell out this ratio. The EMA also says that 10% of commercial batches should be tested, while the FDA does not have guidance on the number of batches to be tested.

At Teva api, we develop and validate highly sensitive analytical methods for confirmatory testing, utilizing machines such as GC-MS 3Q or LC-MS 3Q.

Our methods are developed to monitor specific Nitrosamines which according to the process in question could potentially be present in each API in line with all the current regulations and best-practices.

Submitting a change

Once the risk assessment activities have been completed, you’ll have a clear idea of what changes need to be implemented. For example, you may need to change the manufacturing process by adding an extra purification stage, adjusting a process, or adding a new step. You may also need to make changes to the premises or the equipment you use.

You’ll need to validate the specification and method you’ve developed to fix the problem, and ensure that you’ve controlled the change going forward, for example changing a supplier or codifying the new manufacturing process.

Now, it’s time to communicate the changes to the customers, MAH, authorities and to regulatory boards. At Teva api, as an API manufacturer and a CEP holder – we submit these change requests to EDQM, noting whether this is a minor or a major change in process. For example, the inclusion of mutagenic impurity in API specification is a minor revision, and so is any update in the impurity section.

Remember: In relevant case when nitrosoamines risk assessment needs to be added, even if the risk assessment only concludes that there is no risk being added – EDQM still requires this to be submitted as a minor revision (not as notification).

Facts and dates for your diary

• All relevant CEPs should be revised in order to control Nitrosamines by 26th September 2022.
• For US market, DMF amendment include relevant updates should be prepared and submitted to FDA in collaboration with MAH. FDA allows proposed process to be submitted with estimate for removal of the original process. The different synthetic processes should be identified by separate codes.
• Deadline for MAHs to submit changes to FDA is Oct 1st 2023.
• If the original process cannot be discontinued within a reasonable timeframe, the new or revised process should be submitted in a separate DMF.

At Teva api, we work together with our vendors, customers and partners to ensure that we carry out a thorough risk assessment and testing process, ensuring that we have plenty of time to communicate and submit changes before the dates provided.

If you’d like any more information on how we work to control Nitrosamines in our API manufacturing, reach out here, or watch the complete webinar below.

Our recent webinar was about all aspects of cocrystals! We heard from Anantha Rajmohan, Head of Physical R&D India, Diana Skalec Samec, Senior Group Leader for Physical R&D, and Maytal Piran, Director of Global Physical R&D. They spoke in-depth about how to choose the right target for your API, the advantages of using cocrystals, and various regulatory considerations to think about. We also heard about Ibrutinib – an example of cocrystals in action! If you missed the live event – consider this your catch up.

Drug Discovery and Development

Drug discovery and development can take 10-15 years before final approvals, starting with basic research all the way through to an approved drug. Millions of dollars will go into the process, including a large proportion on clinical trials. After selecting the active molecule, 70% of drugs approved by the FDA are solid, so selecting the right solid candidate is very important.

Once the active molecule is identify, the solid-state analysis such as salt and polymorphous search start.

Choosing the right target is no easy task! To start with, the solid form should be stable and reproducible at large scale, and commercially viable, too. The right solid candidate should be stable in stress conditions such as temperature and humidity, which gives good opportunities to the formulator.

Understanding Cocrystals

Cocrystals can be reproducible and can enhance the process of APIs, adding value to the business. In cocrystals, both components are solid at room temperature. This is differentiated from salt by the bonding between the components. In salt there is an ionic charge separation while in cocrystals it’s a hydrogen bonding, a much weaker bond. Depending on the API, cocrystals can be split into four types – cocrystal, salt cocrystal, cocrystal solvate or sulphate, and salt cocrystal solvate. You’ll need a strong characterizing team to differentiate between the types.

In 2018, the FDA defined cocrystals as crystalline materials composed of two or more different molecules, typically an API and coformer, in the same crystal lattice. These can be tailored to enhance the bioavailability and stability of drug products. Interest in pharmaceutical cocrystals is growing, with research and interest increasing steadily over the past decade. Already available in the market are drugs including cocrystals.

You can see the process for the characterization of cocrystals, below.

Regulatory Considerations

This is one of the most important thing to think about in Pharma. For the FDA, cocrystals are classified as a special case of solvates and hydrates and pharmaceutical cocrystals are placed in the regulatory classification similar to that of a polymorph of the API. The chart below can be a helpful resource to explain the main differences between FDA regulation and EMA regulation.

Your regulatory approach for cocrystals should ensure three things. First, that the API and the coformer exist in neutral states, and any interaction between them should be non-ionic and non-covalent. Second, that the value of the ΔpKa should be less than 1, that is ΔpKa [pKa (base) – pKa (acid)] <1. Last, the API and the coformer should be disassociated before reaching the site of pharmacological activity. These three steps are foundational to put you in a good place to gain regulatory feedback.

Deep Dive on Ibrutinib – an Example of Cocrystal Formulation in Action

Ibrutinib was developed by Pharmacyclics and Johnson and Johnson, and was approved by the FDA in November 2013 for the treatment of B cell cancer treatment. It is expected to be third in the best-selling cancer drugs of 2022*.

At Teva api we started developing Ibrutinib api for generic submission by undertaking a literature search, a polymorphic search, and a cocrystal search. We made an evaluation on long-term stability and during the development process, on solubility and reproducibility as well as handling conditions. We found a few crystalline and amorphous targets and started looking into each.

At this stage, we found that our forms weren’t suitable enough for formulation. When you’re evaluating your target, you should look out for some parameters such as limited physical and chemical stability, sensitivity to production process, solubility, handling, and limited crystallization options to control morphology.

We then initiated a cocrystal research. During the search of coformers, we found several options, going back to the lab in order to prepare them. After characterization we found three options for a cocrystal in terms of a coformer, Benzoic, Succinic and Fumaric acids. We tried to prepare these on a high scale, and finally Ibrutinib Hemi Fumaric Cocrystal was found to be the most appropriate target..

Teva api’s Ibrutinib has a robust process, long term chemical and physical stability. During the time that we were working on Ibrutinib, we followed the FDA guidelines to apply for regulatory support. Following all regulatory requirements, we submitted our DMF in the US. We got FDA tentative approval, and the FDA has even used our DMF for Ibrutinib as an example of cocrystal characterization!

Key for Success with Cocrystals

• Deep chemical and analytical understanding: This was the most important element for our own success. Really know the product.
• Agility in development: Be able to test candidates in parallel and to change quickly from one to another where needed.
• Collaborate meaningfully: Communication across supporting units including patent , quality control, regulatory affairs and marketing teams.
• Customer-focus: Constant communication, sharing knowledge and updates with your customer as necessary.
• Data sharing: Think about what kind of knowledge you can provide to assist the formulator, or if you’re asked to provide additional information.

To catch up on the full webinar, including learning about the challenges of choosing a conformer, the different strategies and advantages of cocrystal formation, and the benefits of using cocrystals over other alternatives, plus the informative Q&A session, watch the whole on-demand webinar below.

The information contained herein is the confidential and proprietary information of TEVA PHARMACEUTICAL INDUSTRIES LTD. and its affiliates. The information contained herein is provided as courtesy only, and should not be considered in any way as legal, regulatory or otherwise professional advice. You should seek appropriate professional counsel for your own situation and requirements. No representations or guarantees whatsoever are intended to be given by TEVA PHARMACEUTICAL INDUSTRIES LTD. Teva makes no warranty as to the completeness or accuracy of the information provided herein. Furthermore, no information in this presentation, including any reference to any product or service, constitutes an offer for sale, or should be construed as representing an offer for sale. Specifically, no part of this presentation should be construed as a promotion or advertisement for any product, or for the use of any product, that infringes valid patents and/or is not authorized by the laws and regulations of your country of residence.