Process Analytical Technology (PAT) in Pharmaceutical Manufacturing

In today's competitive world, one must constantly evolve to mark their place. Needless to say, it is all more vital for the pharmaceutical sector. Isn’t it? So, how can a drug formulating company shine in the crowd? The answer lies in innovation and application of new technologies. One such example of innovative technology is Process Analytical Technology or PAT. 

The need for PAT stems from the fact that pharmaceutical companies constantly require technological innovations to meet the market demand. Their primary aim is to deliver effective and precise active pharmaceutical ingredients (API). The manufacturing of API is a complex and technique-sensitive process that requires consistent sample collection and analysis.

But how does the Process Analytical Technology ensure the consistent quality of the pharmaceutical end products? And is it beneficial for pharma professionals to implement this technological process in their existing manufacturing units? Let's find out in this article.

Introduction

The quality of the manufactured drug is the prime concern of any pharmaceutical company. Conventionally, quality control during the pharmaceutical manufacturing process was based on statistical process control (SPC) to eliminate the source of variation to maintain a stable mechanism. However, SPC (statistical process control) did not solve all quality-related issues, for instance, the quality of intermediate products couldn’t be assured through SPC.

To overcome this shortcoming, the pharmaceutical companies introduced Quality by Design (QbD) to streamline the quality control process during drug manufacturing. Based on science and quality risk management, the QbD predetermines the quality control objectives at each step. To accomplish the QbD principles, Process Analytical Technology (PAT) was introduced in September 2006 by the US Food and Drug Administration (FDA).

PAT is an innovative technique that designs and controls the manufacturing processes in the pharmaceutical sector to monitor the critical process parameters(CPPs) involved in the formulation of API.

By incorporating PAT at each unit operation, pharmaceutical companies can effectively control CPPs and Critical Quality Attributes (CQAs), ensuring high-quality end products. This integration not only upholds the QbD framework but also enhances overall manufacturing efficiency and product reliability in the pharmaceutical industry. 

This blog will provide a comprehensive guide on the implementation and benefits of PAT for pharmaceutical professionals.

The Role of PAT: How PAT ensures process consistency and quality

PAT believes quality should not be tested at the product level but must be built into the design. It effectively monitors the reaction paths and thus develops a better understanding of the manufacturing and building of a robust and safe process. Process Analytical Technology has several elements that work in coordination to ensure the manufacturing of quality products. The major requirements of this process are:

Regular improvisation and knowledge management

PAT involves continuous data collection and analysis for knowledge enhancement. The scientifically backed data collected justify the post-approval process.

Process Monitoring and Internal Controls

PAT includes regular monitoring to increase the product yield and maintain quality and consistency. Moreover, this step also aids in reducing the rejects and waste material. Consistent control checks improve investigations, enhancing the quality of active pharmaceutical ingredients.

Real-Time Testing

With PAT, laboratory expenses decrease, as does inventory, and production cycle time while enhancing batch quality assurance. 

Additionally, the ample data accumulated through PAT allows rapid resolution of problems. It becomes easy to detect and optimize the flaws in the manufacturing process and identify the root causes of undesired quality products. Therefore, appropriate implementation of PAT helps prompt modifications of problematic parameters, reduces manufacturing time, and guarantees quality products. 

Another approach to ensure consistency and quality is using measurement methods. These methods are of three types- at-line, on-line, and in-line. 

The at-line method- Involves the collection and analysis of a sample from a place near the manufacturing unit. The major advantage of this method is it waives off the time delays.

The online method- It is utilized to gauge the manufacturing sample, assess its suitability and discard unwanted samples.

The in-line method- In contrast to the on-line method, the in-line technique doesn't involve collection of samples. Instead, it is a real-time monitoring that uses software for the collection and measuring of samples from the process which is analyzed using statistical equations. It gives better control of the entire drug manufacturing process.

PAT Techniques: Overview of key PAT techniques and technologies

Pharmaceutical companies have to meet the high expectations of both regulatory bodies and patients to certify their manufacturing process and the quality of their formulations. Thus, these strict requirements and several constraints require relevant monitoring and control processes. However, Process Analytical Technology resolves these difficulties by application of real-time experimental and analytical tools. 

However, many available tools enable risk management, quality assurance and scientific approaches to pharmaceutical manufacturing processes. Concerning the PAT, these tools can be broadly categorized as: 

Multivariate data acquisition and analysis tools-

Pharmaceutical manufacturing is a multifactorial-complex process. Accurate knowledge is mandatory for designing procedures that provide suitable operating conditions to extract the best formulation. In addition, most pharma companies apply mathematical multivariate methodologies such as statistical designs, pattern recognition tools, response surface methodologies, etc. 

Moreover, statistical principles of orthogonality, reference distribution, and randomization underpin methodological studies, such as factorial design experiments, which offer efficient ways to discover and examine the relationship between process and product variables.

Throughout a product's life cycle, experiments are carried out to create new products. Processes can act as building blocks for knowledge that will eventually expand to accommodate a higher degree of complexity. Data from these controlled tests help build a knowledge base about a specific product and its operations. 

This data can then be incorporated into an overall institutional knowledge base, together with data from other development programs. It will be possible to mine this institutional knowledge base to find patterns that will be helpful for the next development projects as it expands in coverage (number of variables and scenarios) and data density. 

Additionally, these experimental databases can facilitate the creation of process simulation models, which can speed up development overall and promote continuous learning. 

Analytical chemistry tools/Modern Process Analyzers-

Owing to the increasing value of the collection of process- samples during production has led to the development of analytical chemistry tools. Modern instruments that assess physical characteristics and chemical composition have developed from basic process measurements like pH, temperature, and pressure. These days, process analysis technologies are available that are non-destructive and can measure the physical and chemical properties of the material being processed.

Traditionally, such measurements were done off-line in the laboratories. However, these measurements can now be performed via in-line, on-line or at-line methods. The recent real-time innovative methods provide easier and guaranteed methods to obtain quality products, but mathematical multivariate analysis is necessary to correlate the obtained results with primary analysis. 

Other tools that fall under the umbrella of the PAT framework are process end-point monitoring and control tools and continuous improvement and knowledge management tools. These tools monitor and ensure a stable link between the product design and manufacturing for effective control of the critical quality attributes. This also helped gaining and accumulating scientific data to the existing and future manufacturing proposals respectively. Knowledge tools also aid in promoting the communication links between pharma companies and regulatory bodies.

The Commonly used PAT tools-

Many PAT tools from the above-mentioned categories have already marked their efficiency in the market. Let us brief on some of the other successful tools-

Infrared spectroscopy-

Out of the three regions of the infrared spectrum, the near-infrared vibrations (14000-4000 cm-1) are used in the PAT framework. These radiation transmittance and reflectance properties are used for quantitative and qualitative analysis. These are often used as real-time imaging tools for quality control and assurance in drug manufacturing units. 

Real-time monitoring quality is enabled because the NIRS is attached to a fiber optic probe, allowing for non-destructive measurement of the product's quality during the process through the sample's transmission and reflection of the NIRS. Multivariate statistical analysis is commonly applied to extract the quality assessment. 

However, due to the spectral complexity, overlapping bands can make result interpretation tricky. Therefore, infrared spectroscopy is often considered a relative tool that requires a reference method when corrections are demanded. 

Raman Spectroscopy-

A type of vibration technology, Raman Spectroscopy is provisioned with an optic laser involving a wide range of spectrum ranging from ultraviolet to near-infrared and a charged couple device (CCD). Its extensive use in the pharmaceutical sector is because of its quick analysis of the chemical composition and structure of a solid, liquid, gas, gel, or powder sample by examining the specific properties of their vibrational transitions. 

This PAT tool is employed to identify the molecules present in a sample, and the magnitude of their intensities allows for quantifying the drug concentration in that particular sample. One of the biggest advantages of Raman Spectroscopy is its ability to operate both online and in-line. 

Moreover, interpretation of the results is much easier than the infra-red technology, which can be easily accomplished by simple modeling between peak heights and ratios. The PAT tool ensures precise and consistent monitoring of the manufacturing process in real-time, both quantitatively and qualitatively.

Hyperspectral Chemical Imaging-

Hyperspectral Chemical Imaging combines infrared spectroscopy with digital imaging to provide both spectral (like identifying chemical composition) and spatial (like seeing where those chemicals are) information within a single framework. Hyperspectral imaging (HCI) can be utilized throughout a spectrum of wavelengths from 1000 to 2500 nm. 

Also, it is a non-destructive analyzing tool that supplies chemical and spatial imaging information during various manufacturing steps like blending, granulation and tableting. HCI is specifically used as an on-line technique to surveil blending and tablet instability.

Terahertz Pulse Imaging (TPI)- 

The Terahertz Pulse Imaging tool works in the spectral range of 0.1 -- 4.0 THz (between infra-red and radio wave frequencies). Owing to a long spectral coverage and lower radiation energy, there is less scattering during the interaction with the drug molecule, thereby reducing the damage. The TPI tool is mainly used for real-time imaging, and for assessing the tablet surface and coating. It is specially used to control the manufacturing of sustained-release tablets where the thickness of the tablet coating determines the drug release.

Acoustic Resonance Spectrometry-

Acoustic Resonance Spectrometry (ARS) is another PAT tool that is non-invasive and requires no sample preparation. However, in contrast to spectrophotometric technologies, ARS works by assessing the sound waves generated during drug manufacturing. The ARS PAT tool is most commonly put in application to the chemical processes that emit acoustic radiations, such as pulverization, blending etc. 

For example, during the granulation phase, drug particles produce sound waves causing friction in the apparatus. Similarly, acoustic tools are also used in-line during crystallization processes, providing details regarding the dispersed liquid and solid phases in the suspension. These tools also highlight the moisture content and particle characteristics in the drug formulation. 

High-Speed Digital Imaging-

High-speed digital Imaging is a rapid, non-invasive method that requires digital equipment such as a digital camera, optical illuminating tools and algorithms for capturing real-time data. PAT tools based on digital imaging are usually applied to decipher the size and shape of crystals during the crystallization process. 

Several factors determine the quality of the result obtained such as the lens of the digital camera, shutter speed, exposure time, homogeneity of illumination, temperature drift etc. The speed at which the digital images are captured ( determined in terms of frame per second(FPS)) also regulates the quality of obtained information. 

Attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy-

ATR-FTIR spectroscopy functions at the mid-infrared range. Total internal reflection occurs at the crystal and material interface during its(high-refractive index) interaction with the probing crystals(low-refractive index). This is termed “multi-bounce ATR-FTIR '' which has a high signal intensity and signal-to-noise ratio adding to its advantage. 

In the pharmaceutical sector, its main application is in the form of in-line monitoring. Attenuated total reflectance- Fourierrier transform infrared spectroscopy is widely used to regulate solute concentration and supersaturation in batch cooling crystallization.

Spatial Filter Velocimetry, Focused Beam Reflectance Measurement (FBRM), X-ray fluorescence (XRF), and Microwave Resonance Technology (MRT) are some of the other less popular PAT tools that produce useful data required in the quality control process. 

Chromatographic techniques such as Ion-Exchange Chromatography (IEC) and Size Exclusion Chromatography (SEC) are useful in measuring Critical Quality Attributes such as heterogeneity charge and protein aggregation.

Challenges and Future Directions: Challenges facing PAT adoption in pharmaceutical manufacturing

With constant development in the pharmaceutical sector, focus on quality production is gaining more importance than ever, especially since the world faced the pandemic COVID-19. PAT is one of the best ways to combat the challenges concerning the quality control of pharma products. 

The Benefits of Implementing PAT-

Adapting the PAT technology has several benefits- 

• Reduces processing cost
• Brings uniformity to the end product
• Reduces product change-over time
• Wards off rejects and repeats in drug manufacturing

The Constraints-

Despite amazing results, some constraints hold back pharmaceutical companies in accepting and enforcing the PAT technology. Let’s understand what are the key constraints that block the full-blown implementation of PAT- 

PAT is not an object to be implemented but a working principle to be adapted at individual and manufacturing levels. It is a framework to design and develop detailed and accurate processes that will ensure quality products. Therefore, the hardest barrier to overcome is the mindset and a decade-long work culture that focuses on improvising mistakes instead of modifying processes. 

Other hurdles that obstruct the growth of PAT are

• Time-foundations
• Budget concerns
• Staff limitations
• Specialized analytical skills
• Statistical knowledge
• Lack of availability of real-time technologies
• Internal disagreements over PAT value
• Speculations on the usefulness of spectroscopy

The Brighter Side- 

Although there are buckets full of challenges, the adaptation of PAT by the pharma sector is on the rise. Process quantification and Process Analytic Techniques are being made easier by ongoing advancements in sensors, probes, and analytical tools. The generated data will enable mathematical modeling and risk analysis more and more when bioprocessing is monitored by better chemical, physical, and microbiological detection methods and assays, including single-use sensors/probes. 

Industrial adoption is expected to rise as PAT is acknowledged as a useful technique for raising yields, decreasing waste, enhancing productivity, increasing automation, and supporting other cost-cutting initiatives. Put another way, once it is generally acknowledged that PAT results in long-term cost savings, implementation will accelerate.

Conclusion

In conclusion, Process Analytical Technology is an essential tool for bioprocess-based industries seeking to develop high-quality goods while meeting the evolving needs of users and ensuring their safety. The variety of PAT tools such as multivariate and chemometric techniques, and spectroscopic, and imaging technologies, equips professionals with invaluable insights. 

Moreover, PAT improves understanding of raw materials by characterizing them chemically and physically affecting manufacturing parameters and the quality of the final product. Combining these elements results in more reliable processes, improved product quality, better process control, and time savings. It finally leads to significant cost savings and helps build a distinctive brand image for the company.

As the industry transitions from post-production quality testing to a Quality by Design approach, the relevance of PAT will continue to increase in the pharmaceutical sector.