The generics market has been very attractive for pharmaceutical companies for the last few decades. But as this market is becoming more and more crowded with simple generic products, leading biopharma companies are starting to focus on complex generics.
The respiratory segment is a good example of complex generics. This blog will delve into them and discuss the expertise required from an API company to develop this technology successfully.
This blog is part a full whitepaper on complex generics.
Over the past few decades, there has been huge growth in the number of non-cancer respiratory diseases. Asthma medication for example is projected to rise from 10% of the respiratory market in 2019 to 23% by 2024, while other Asthma or allergy related medication will rise from 21% to 26% during the same time period.
According to Pharma intelligence, it is estimated that – asthma affects ~350 million people worldwide, 25MM+ in the US alone, including 6MM children. On top of that, COPD is estimated to impact 315MM people in the world, with 13MM in the US diagnosed, and 24MM with impaired lung function.
The chemical, physical and bulk properties of APIs for respiratory formulations are especially important and dramatically influence the behavior of the API during the formulation process, and more importantly the performance of the drug product during treatment.
(Images taken from Pharma Intelligence)
Types of Delivery Devices
Respiratory drugs present a unique set of challenges, because most of them are delivered through inhalation as powders. That means that the API has to be broken down into fine particles through a process called “micronization“.
Once developers have created a suitable powder, the next issue is finding the right delivery device to get it into the lungs.
There are a few types of devices:
- Dry powder inhaler (DPIs) that contain a powder made up of the API and a carrier, usually lactose particles. The patient inhales a really big breath in, so that the full dose gets to their lungs. For some patients, this may make a DPI more or less difficult to use during an asthma flare¬-up.
- Metered dose inhalers (MDIs). A blast of medicine is delivered by pressing a button. They are aerosol powered and deliver a fixed dose using an HFA, or hydrofluoroalkane, propellant.
- Soft mist inhalers which create a cloud of medicine that can be inhaled without the help of a propellant or lactose.
Shapes & Sizes of Particles
In general, API doses might range from several milligrams to around one gram. But for respiratory APIs administered by inhalation, doses are tiny, usually only a few micrograms – which is hundreds of thousands, if not up to a million times smaller than a regular API dose.
These APIs allow a much smaller margin of error when developing products for specific inhalation devices. Therefore, a range of techniques is needed to do a full physical characterization of each API and each product.
One of the most important things to think about for respiratory APIs is the shape of the particle. Obviously API particle shape and size will impact particle surface area.
For example, some particle shapes, like needle shapes, don’t stick very well to the carrier used in the dry powder inhalers. And that means they often don’t reach the right part of the lungs. The more suitable shape for respiratory API is a round shape or regular shape particles which has optimized aerodynamic properties, so we can expect they reach the right place in the lungs.
Another thing to consider is particle size. The idea is to create just the right size of particle to reach the right place in lungs and be deposited there effectively. So for DPI formulation, for example, particles with a mass median aerodynamic diameter of below 10 micrometers is ideal.
Those particles reach the right part of the lungs, through the bronchial tree and alveolar regions, and are deposited there. Any larger, and the particles end up stuck in the airways or mouth, or even swallowed. Any smaller and they tend to be exhaled before they’re deposited, which means that they don’t have a chance to work.
In the end, the majority of all respiratory particles of API are lost this way. Of course these variables cannot be eliminated entirely, but they need to be considered when developing the API drug substance.
But it’s not only the shape and size of particles that matters. All sorts of other factors need to be examined during the development process. For example, most drugs come in a crystalline form, and could potentially exist in many forms.
These are known as “polymorphic forms” and there can be huge differences between them, which have significant implications for pharmaceutical applications — everything from physical properties, product stability, solubility to formulation aspects.
This has a huge effect on how the drug works — how effective it is, e.g. bioavailability. It’s also important to look for amorphous traces, which are traces of non-crystalline material with potential impact on API solubility and stability. Obviously amorphous content needs to be controlled.
At Teva api, we quantify it via various analytical instrumentation e.g. thermal techniques like modulated differential scanning calorimetry, microcalorimetry and others to measure amorphous content in our products. However even more important is to set micronization parameters in order to minimize amorphous matter creation.
In addition, we have developed specific processes how to remove amorphous matter completely from the final product. This is a unique know-how which makes our final API much stable in terms of physical properties during manufacturing and its storage.
To ensure the right particle size, the API goes through a process of micronization, which means breaking down bigger crystals into a fine powder.
At Teva api, our scientists and engineers are always working to optimize our particle size reduction techniques. Because we perform this development internally, it gives us better control over the process, and also greater flexibility. Really it’s about being able to tailor solutions to each customer’s exact needs.
The first point for perfect micronized product is the crystalline API for milling or micronization. Therefore, we optimize crystallization in all aspects in order to have consistent particle size and morphology.
Our Center of Expertize in Europe has various technologies for size reduction available in one place. Among our technologies are various types of milling, micronizations with QbD approach.
Our experienced experts are exploring all possibilities to find the right technology and equipment for our products. When we find the optimal technology and conditions we perform technology transfer to production site and verify again the final product quality.
Since particle size is so important for respiratory drug product, we can provide tailor-made particles for each customer‘s formulation development. We can provide several grades of particle size for testing the right target during pharmaceutical development.
Once the right particle size is found adequate for formulation, we continue to work on monitoring other physical properties.
Flowability and Bulk Properties
Flowability means whether particles flow freely over each other. This is tested by a special machine called a powder rheometer. By measuring the powder’s resistance to the probe, you can see whether the API flows well and is suitable for formulation, or tends to stick together, which can cause some trouble during formulation and storage. Examining bulk and tap density is also crucial and may impact how the powder will behave during processing and storage.
Respiratory APIs & the Teva api Advantage
Teva api has a variety of respiratory APIs and our R&D team is invested in developing an in-depth understanding of the formulated API. We look at everything from manufacturability and stability to legal issues, and factors that could affect formulation development.
We offer a complete support package on the sales side of things, but that obviously has to begin with research and development.
We have approximately 15 different respiratory APIs across all therapeutic categories, making us a leading supplier in this sector. The respiratory segment is a hugely important one right now. So we’re really going the extra mile.
All our respiratory APIs are produced in state-of-the-art facilities both in R&D and in production. We can work with highly potent APIs, including steroids. We have the personnel, the expertise, the equipment, and decades of scientific experience.
Tools such as Design of Experiments methodology, computational tools, modeling, and Process Analytical Technology help the team design, analyze, and tightly control manufacturing processes. And this ensures the highest quality products.
Our respiratory portfolio has been the largest in the industry for some time, and we’ve just added four newest products for pharma R&D development.