Industry-4-0, Pharma-4-0 31 March 2022
NIR technology and Raman spectroscopy: introduction and applications in the pharmaceutical industry
NIR technology and raman spectroscopy
Share post

In the following article we will address the main applications with NIR technology and Raman spectroscopy, in real time, for the control of manufacturing and quality processes both for pilot plant – in tune with the Quality by Design (QbD) concept – and for industrial scale-up. In addition, this article is intended to be a starting point for industry professionals to raise questions about how to optimize control with process analytical technologies (PAT) for efficient management and implementation of a continuous manufacturing model.

 

Raman and NIR Spectroscopy

 

Both technologies have in common that they are photonic techniques – they take advantage of the properties of photons or light and their interaction with matter – diagnostic and non-destructive, allowing chemical and structural information to be obtained in seconds from almost any organic or inorganic material or compound. Hence, their use in laboratories is widespread in different industries and they are analytical techniques known by quality control professionals.

 

For those who are not laboratory professionals or are just entering the field, it is essential to start with a few brief concepts and examples to understand its applications.

 

Raman spectroscopy is a technique based on the inelastic scattering of light. Inelastic or Raman scattering occurs when the energy changes during the collision between the monochromatic light and the molecule and, therefore, the frequency of the scattered light also changes. These changes provide information about the molecular identity and structure of the samples or material being analyzed.

 

Near infrared spectroscopy (NIR) is a technique based on the interaction between electromagnetic radiation and matter, within the wavelength range of 780-2500 nm. These absorbed radiations can be related to different properties of the sample, providing qualitative and quantitative information. The near-infrared range is characterized by weak overtones and combined bands arising from the strong fundamental vibrations of O-H, C-H, C-O, C=O, C=O, N-H bonds and metal-OH groups in the mid-infrared range.

 

However, both Raman and NIR spectroscopy devices in real time are optical (vision) devices that work with artificial intelligence. The information they collect from the spectrum of the analyzed object is interpreted by a mathematical model – chemometrics – called a “predictive model” that tells the system what it is looking at. A very simple example: if we want to control the Paracetamol content of a 1mg. form, the mathematical model that analyzes the process must know how to correlate the spectrum corresponding to that value and for that it must know what is 0.8 – 0.9 – 1.1 and so on in the range of interest to be controlled. The predictive model is a mathematical model that essentially correlates a spectrum with a reference value. This reference value comes out of the traditional laboratory analysis.

 

Let’s get down to the important: What use are these systems in my factory?

 

Applications of real-time NIR technology:

 

1) Raw material identification: Identification of raw materials is a routine task in the pharmaceutical industry. These tests are carried out before the materials are processed, in order to avoid errors as much as possible and thus save time and money. This material testing applies not only to purchased materials (e.g. excipients), but also to some internal material transfers, e.g. APIs manufactured in another plant. The latter is very important to take into account when wondering why we have problems in mixing some formulations with certain raw materials.

2) Homogenization: Once identified and weighed, raw materials usually require homogenization of the different components. This is a critical step in the manufacture of solid-state pharmaceutical products, as it has a direct impact on the quality and homogeneity of the final product. The homogenization process is mainly affected by physical properties such as particle size, shape and density. Mixing endpoint and homogenization are not the same, not in terms of regulation according to the European Medicines Agency (EMA). From IRIS Technology we try to raise awareness on this point, which is sometimes confused, to provide in-line control solutions that are homologous to the control protocols established by the EU and Spanish regulations.

3) Granulation and sizing: Sometimes the different ingredients of the formulation do not mix well and segregate during homogenization. Therefore, it is desirable to granulate powdered ingredients by compression, dry granulation or in the presence of a binder under wet conditions. Most spectroscopic uses focus on the determination of water during wet granulation or drying after granulation.

4) Extrusion: NIR spectroscopy has been widely used in hot extrusion to monitor both API content and solid state of extrudates and to identify interactions between ingredients.

5) Tableting: This stage of the process is the closest to the final product. Therefore, it is sometimes easier to control the quality of the product directly in the press, especially if there is a subsequent coating step. At this point, NIR can also play an important role.

6) Coating: The coating process is a crucial step in the manufacture of solid oral preparations. In fact, the coating can act as a physical screen to avoid the effects of oxidation, moisture and lighting conditions in order to improve the stability of the final product or intermediate products in the process. The coating can also play an active role in the protection (gastroresistance) and release (modified release) of the drug in vivo. The homogeneity and thickness of the coating are important in controlling the timing of drug release. Many offline techniques are available to control the coating thickness, such as changes in weight, height or diameter of the coated granule/tablet cores during processing. In-line NIR technology is especially useful for monitoring water-based coatings and is a technique that saves hours of analysis, which we have discussed in particular in this other article.

7) Final product control: An important part of final product quality control includes the analysis of all batches produced to avoid out-of-specification results. This control point, although it is too late to avoid losses, can also be performed with portable (handheld) NIR tools and in just seconds analyze dozens of units (homogeneity, concentrations or other parameters) at the line.

 

Real-time Raman spectroscopy applications

 

As we will see below, this analysis technique has some applications similar to NIR spectroscopy and others very different because it is a technique with a much higher precision than NIR and that IRIS Technology uses in the systems we manufacture when we work with APIs with very low concentrations (typically <0.5) or in aqueous matrices where the amount of water generates a lot of noise in the analysis with NIR equipment.)

 

1) Raman spectroscopy for API identification: As each API has its own Raman characteristics, Raman spectroscopy can quickly and accurately identify the active ingredients, has a very low prediction error and in some cases has a detection limit as low as ppm.

2) Raman spectroscopy for the quantitative and qualitative analysis of formulations: The composition of pharmaceutical preparations is relatively complex; however, Raman spectroscopy remains one of the rapid detection methods if the excipients are simple or just an aqueous solution.

3) Raman spectroscopy for detection of illicit substances: Raman spectroscopy can be used for trace detection due to its sensitivity, speed and accuracy. In general, small amounts of illicit drugs cause drug safety incidents, and Raman spectroscopy can be used for illicit drug detection.

 

Benefits of applying NIR and Raman technology in production lines

 

In general, there are two fundamental advantages of Raman spectroscopy and NIR technology on production lines over traditional laboratory methods:

 

The first advantage would be the monitoring of continuous manufacturing. The pharmaceutical industry works mainly in such a way that the final drug is the result of several independent production steps. These can also take place in different geographical areas, which entails shipping and storing the different intermediate products in containers until the next manufacturing facility. This increases the risk of degradation over time or due to environmental conditions (light, humidity, etc.). One way to address this problem is to move from independent batch work to continuous manufacturing with the help of monitoring technologies such as real-time analytical control equipment.

A continuous process or continuous manufacturing is one in which materials are continuously loaded into the system, while the final product is continuously unloaded. Unlike stand-alone batch manufacturing, this concept involves the total connection of production units, with the use of PAT systems, along with process control systems to monitor and control the integrated manufacturing plant. Continuous process units are usually more efficient, more productive, with reduced volumes and less waste compared to classical process units. Therefore, these types of production units can respond more quickly to drug shortages or sudden changes in demand or needs (such as in a pandemic). In addition, their small size allows them to be transported directly to where the drugs are needed. However, a thorough understanding of the process, including the different connections between its processing units, is necessary.

The second major advantage is to reduce sampling and analysis time, and this is very important in biotech processes in their research, development and production phases. So far, most of the data are obtained with off-line instruments and methods.

 

Specifically for Raman, Raman spectroscopy is a powerful instrumental technique used in various types of pharmaceutical analysis. The superiority of the technique depends on the molecule of interest, the concentration level, the matrix or solution, other interfering species present and the desired sampling method. For many applications, Raman spectroscopy may be the best answer for identification and spectroscopic control needs. The role of Raman spectroscopy as a quantitative analytical tool is increasing due to the simplicity of sampling, ease of use and applicability to aqueous systems.

 

As manufacturers and system integrators of systems that operate with Raman and NIR spectroscopy, IRIS Technology collaborates with numerous pharmaceutical, foodstuffs, chemicals, among others, companies in the development of analytical solutions and the implementation of control systems, in turnkey projects ranging from technology, adaptations that may be necessary, data modeling, installation, validation and even homologation.

Here you can find the complete range of Visum® analytical equipment.

We hope this article has been of interest to you and as always, if you have any questions or even suggestions, you can write to us at news@iris-eng.com.

By IRIS Technology Solutions
Big-data, Digitalization, Pharma-4-0 2 February 2022
Artificial Intelligence as a Predictive Maintenance tool
Predictive Maintenance
Share post

Together with the company mAbxience, specialized in the development, manufacture and marketing of biopharmaceuticals, we developed data models based on supervised machine learning techniques that after 4 years of work resulted in an AI-based Predictive Maintenance System in the plant facilities of the water for injections (WFI) process of mAbxience in Spain, published in the January-February Edition of the Pharmaceutical-Engineering Magazine.

The work demonstrates the effectiveness of machine learning models, built from the information generated by 31 sensors, 14 alarms and water quality indicators, to identify and predict anomalies within a warning time window (14 days) that is feasible for the preventive and predictive maintenance teams to make the corresponding adjustments in the areas and components of the plant identified by the algorithm.

Initial results show that the models are robust and able to identify the chosen anomalous events. In addition, the rule induction approach to machine learning (a technique that creates “if-then-else” rules from a set of input variables and one output variable) is “white box”, which means that the models are easily readable by humans and can be deployed in any programming language.

IRIS thanks mAbxience and the WFI plant technicians for their collaboration.

Read the full article here.

By IRIS Technology Solutions
Digitalization, Industry-4-0, Pharma-4-0 10 January 2022
Monitoring the pharmaceutical pellet coating process?
monitoring of the pellet coating process
Share post

In the pharmaceutical industry, there are many microgranulated formulations that are coated to achieve a sustained release or a controlled release of the drug or active ingredient over time, a clear and well-known example is Omeprazole. In this article we will talk about these formulations and how to avoid, during the coating process, release and potency analysis using NIR technology. At the end we will explain a concrete case of application.

During the pelletization process of modified release dosage forms, the correct application of the coating (e.g. enteric release coating) will determine the subsequent efficacy of the drug and the mg/API release time of the drug. Because of this, controls are performed throughout this process to ensure the quality and thus the expected pharmacological action.

Currently, this control is performed during coating with samples taken from the coating equipment at different times and analyzed in the laboratory using HPLC or liquid chromatography techniques. This method requires sample preparation prior to analysis, specialized personnel and consumables (materials) for analysis. The main problem with the traditional method of control is that it takes a long time to obtain the results and therefore does not allow rectifying the coating process in case of failures or, if the process has to be stopped, the quality of the semi-product may be altered.

An alternative and very effective tool that allows real-time monitoring of the coating process is the NIR technology, since the spectral signature of each pellet can be related to its coating conditions, dosage and release times without the need to resort to traditional methods.

Application case

An industrial application case with a major pharmaceutical laboratory manufacturer of microgranulated formulations showed that there is a clear correlation between NIR spectra, release times and potency (mg API/g pellet) that is released. In this case, an at-line control with a Visum Palm portable NIR analyzer is currently used.

For the elaboration of the predictive chemometric models it was necessary to take samples throughout the coating process from different batches directly from the coating equipment where both wet and dry samples were measured with the portable NIR analyzer.

Subsequently, release and potency tests were performed on the same samples and preliminary predictive models were developed by correlating the NIR spectra with the values obtained by the traditional tests, resulting in a correlation coefficient (R²) of 0.99. These predictive models showed that, on the one hand, it is not necessary to dry the samples for the prediction – so the control can be performed directly on the wet sample – and on the other hand, that there is a clear relationship between the NIR spectra and the release times of 1h, 4h and 7h. Finally, the wet sample model was further robust and tested with more samples and remotely installed on the customer’s Visum Palm portable NIR analyzer, which as a result of the project was able to perform the coating and release potential control at-line in just seconds and without dependence on laboratory HPLC analysis.

We hope you have found this information on the applicability of NIR spectroscopy for monitoring pellet coating quality useful and invite you to send us any questions you may have on this or other applications to our email news@iris-eng.


Joel Valdés Bravo
Technical Disclosure
IRIS Technology | Visum

 

By IRIS Technology Solutions
Industry-4-0, Innovation, Pharma-4-0 27 October 2021
Pre-release: The new Visum Raman analyzer will go on pre-sale to a small number of pharmaceutical companies.
Share post

IRIS Technology presents in the latest edition of Farmespaña Industrial Magazine – Farmaforum Special – its line of PAT analyzers for the pharmaceutical industry with a great novelty for the industry, the expectation for the launch of its Raman analyzer, which will be available both to work at-line or integrated to the line, for the beginning of next year, and whose official launch will begin with a pre-sale stage to a limited number of Spanish pharmaceutical companies.

 

“Our industry knowledge and PAT experience have led us to develop this new member of our Visum family of spectroscopic analyzers, mainly to meet many needs for in-line formulation control, where the particularities of each project and the chemometric modeling work behind each one of them is extremely complex,” said Alejandro Rosales, Science and Technology Manager at IRIS.

 

IRIS Technology’s technical teams are currently working on expanding Raman analyzer applications to processes at different stages of the drug manufacturing industry prior to launch, and invite pharma companies interested in particular applications to perform ad-hoc modeling at no cost.

 

Visum Raman achieves a signal-to-noise ratio far superior to its market competitors because, thanks to its temporal resolution, it physically mitigates the undesirable effects of fluorescence, making it possible to extend the range of applications in the pharmaceutical industry beyond identification.

 

“It is important to us that the Visum Raman, like its NIR siblings, is strongly oriented to the process and production industry, and helps operators and technicians in the factory to make technological decisions at the line and in real time. For this reason, we have already been collaborating with some companies in response to particular challenges, but with a strong transversality to other products and processes. In relation to the reasonable technological uncertainty that this type of industrial-scale projects always generate, at IRIS we work under the “proof of concept” scheme, i.e., we previously validate the success of the project on a reduced scale and in comparison with the criteria agreed with the client”, remarked the Deputy Director of IRIS, Joan Puig.

 

Do you have a challenge for our Raman analyzers? Do you want to participate in the pre-sale? Write to us here.

 

By IRIS Technology Solutions

IRIS Technology presents in Farmespaña Industrial applications of its PAT analyzers for the pharmaceutical and dermo-cosmetic industry.

Real-time content uniformity.

Real-time bioavailability.

Fluorescence-free Raman.

Read the complete note here.

By IRIS Technology Solutions
Digitalization, Innovation, Pharma-4-0 3 June 2021
IRIS presents its VISUM® real-time quality monitoring devices for pharmaceutical companies.
NIR and Raman Spectroscopy
Share post

Read the complete press release in Farmespaña Industrial “Especial Ingeniería Farmacéutica” about the new NIR and Raman Spectroscopy technology used by IRIS in its projects.

By IRIS Technology Solutions