Leveraging Process Analytical Technology (PAT) for OSD Manufacturing

Introduction

Over the last decades Process Analytical Technology (PAT) has been widely used in pharmaceutical development to support process understanding and optimization. PAT facilitates a nuanced comprehension of manufacturing processes, enabling optimization of critical parameters in alignment with stringent quality standards. By peeling back the layers of the manufacturing process, PAT empowers real-time control through meticulous parameter inspection and comprehensive process insights.

• Enhance Manufacturing Efficiency

  PAT enables real-time quality control and analysis at every crucial process, facilitating process control during manufacturing. This reduces the reliance on offline product testing, amplifying production efficiency while ensuring product consistency and minimizing non-conformance. Integration of PAT within the Quality by Design (QbD) framework assuages concerns regarding quality control in continuous manufacturing, fostering a culture of robust production practices.

  
  

• Role of PAT Across Drug Development Phases

  During R&D phase, PAT serves as a beacon for unraveling intricate process dynamics and optimizing critical parameters. For instance, in granulating processes, real-time monitoring of moisture content and granule size variations elucidates the impact of process parameters and material attributes on product quality, thus facilitating informed decision-making.

  
  

  In the technology transfer stage, PAT's prowess shines through real-time data acquisition and comparison with early-stage R&D data. This expedites scale-up processes, minimizes scale-up iterations, and delineates process parameter ranges, laying a solid foundation for seamless transition to commercial production.

  
  

  There are a lot of common PAT tools, e.g. spectroscopy, imaging and laser particle size analyzer. This article intends to introduce the application of PAT in OSD manufacturing, and mainly centers on the application of NIR technology, online imaging technology and online microwave technology.

  
  

• Application of Process Analytical Technology

  1. Near-infrared spectroscopy (NIRS) technology

  NIRS covers the transition from visible light spectral range to mid-infrared spectral range.In the NIR (800-2500nm, 12821-4000m-1 respectively) range, it is mainly generated due to the molecular transition from the ground state to the high-energy level caused by molecular vibration, mainly through the double-frequency and sum-frequency absorption of vibrations of the hydrogen containing groups, such as C-H \ O-H \ N-H \ S-H \ P-H.

  
  

  There are distinct differences in the the near-infrared absorption wavelength and intensity of different groups (e.g. methyl, methylene and benzene ring) or the same group in different chemical environment.Therefore, the near infrared spectroscopy can reflect the composition and structural information of the materials, and can be used for the measurement of the composition and properties of the hydrocarbons. However, as the NIR absorption coefficient is low, and the double-frequency peak and sum-frequency peak of the functional group are superimposed to form a broad peak, chemometrics must be used to obtain information from the spectrogram with a reliance on the computer. The theory about NIR spectroscopy has been expounded in many manuals and papers [1,2].

  
  

  In recent ten years, with the development of continuous manufacturing, PAT has gained wide application, and the application of NIR in batch production and continuous production has also been further promoted.For example, NIR can be used for the identification of starting materials and final products, and for the following inspection of sample bottles, packaging bags, tablets and vials directly due to its strong penetration force: content of drug active ingredients or moisture in various process stages, mixing uniformity during the mixing, granulating or tableting stages, coating film thickness and dissolution, etc. The combination of NIR, Laman spectroscopy and spectral imaging technologies is used for the characterization of the particle size and outer appearance to forecast the granule moisture content, tap density, bulk density and material flowability during the wet granulating process. NIR is a kind of fast and non-destructive PAT technology that now grows rapidly and has broad application prospects.

  
  

  2. Online real-time particle size analysis technology (Eyecon2)

  Online real-time particle size analysis technology is a kind of flash imaging technology, and one ultrashort light pulse will be used for lighting up the moving particles for image acquisition and for accurate inspection of the particle contour to analyze the sizes of the powders and particles; real-time images of the granule sizes and shapes can be generated during batch production and continuous production processes to help the customers learn more about the granulating processes/products, fluid bed coating, fluid bed granulating or drying; and it is used for inspecting the sizes and shapes of granules and pellets during dry granulating, milling, extrusion granulating and twin-screw granulating processes.

  
  

  3. Online microwave technology

  Firstly, microwave is a kind of electromagnetic wave with wave length of 1mm-1m and frequency of 300MHz-300GHz, being fast, time-saving, high efficient, and environment-friendly, so it has become one popular heating method. Microwave technology can be used for inspecting the moisture content in the substances. When microwave penetrates the substances, especially moist substances, water molecule resonance can be caused, leading to the rotation of water molecules at extremely high frequency.The rotation of water molecules will consume some energy, i.e. microwave energy, and the consumed energy is proportional to the moisture content in the substance; therefore, the moisture content in the materials can be calculated by measuring the signal variation of the microwave after penetrating the materials during the transfer process. Microwave can penetrate into the products, inspect the moisture contents on the surface of or inside the materials, and applies to the moisture content inspection of the materials with a certain thickness.

Conclusion:

The integration of NIR spectroscopy, online particle size analysis, and microwave technology exemplifies the transformative potential of PAT in OSD manufacturing (batch production and continuous production). These advanced analytical tools not only provide critical process insights but also pave the way for proactive process control and continual quality improvement. As we research the application areas of PAT in depth, the compilation of case studies will further illustrate its many benefits and highlight its essential role in the modern pharmaceutical industry.

References:

1. D.A. Burns, E.W. Ciurczak (Eds.), Handbook of Near-Infrared Analysis, Revised and Expanded, 2nd ed., Marcel Dekker, Inc., New York, Basel, Hingkong, 2001.

2. L. Bokobza, J. Infrared Spectrosc. 6 (1998) 3–17.