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IJPAR |Volume 3 | Issue 1 | Jan-Mar-2014 ISSN: 2320-2831

Available Online at: www.ijpar.com

[Review article]
Process Analytical Technology
*Satish kumar kengam
Faculty of Life and Social Sciences, Swinburne University of Technology,
Melbourne, Australia.

ABSTRACT
The increasing demand for the better healthcare products has changed the pharmaceutical industry. In the recent
years, the technologies producing the quality products have paved the way for good quality products. The
introduction of new tools and technologies has provided an opportunity for the pharmaceutical producers to
improve the quality standards of the product. PAT is one of the technologies in pharmaceutical production
where they test out the quality of the raw materials, characterize them both physically and chemically, through
at-line, in-line or on-line. PAT saves time and money required for testing and analyzing the products. The PAT
paves the way for making good quality products thus satisfies the customers needs and build a good brand
image for the organization. The two effective tools NIR and RAMAN spectroscopy are used in testing the
quality of the products. This research essay delves the essentials of PAT and the usefulness of process analyzers
in process monitoring. The effectiveness of the PAT tools and the advantages of NIR over RAMAN
spectroscopy are clearly discussed.
Keywords: Process Analytical technology, Raman Spectroscopy, NIR (Near-Infrared Spectroscopy), PAT
tools, Process Analyzers and Process Monitoring.

INTRODUCTION tools and product or process optimization strategies

Process Analytical Technology or PAT is a to manufacture drugs. It concentrates on the
rebellion in the pharmaceutical industry initiated by principles of maintaining quality in the product and
the United States Food and Drug Administration to process as well as continuous process
decrease the risk of producing a deprived quality improvement. PAT encourages continuous process
product (US FDA1). The PAT recognizes and manufacturing improvement like chemical,
manages the manufacturing process, which is physical, microbiological, mathematical and risk
consistent with the current drug quality system. analysis (US FDA2).
The framework of PAT helps to design and Near Infrared (NIR) and RAMAN spectroscopy are
develop the processes that consistently ensure the the tools which have been increasingly used for the
predefined quality at the end of the manufacturing measurements of critical process and product
process. The procedures are consistent with the attributes during the process monitoring. These
quality by design and reduce the risks to quality spectroscopic techniques allow fast and non-
and improve the efficiency. PAT can be defined as destructive measurements without any sample
the optimal application of PAC tools, feedback preparations. Both the techniques are molecular
process control strategies, information management vibration spectroscopy techniques, which help in

* Corresponding author: Satish kumar kengam.

Email: [email protected]
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studying the vibration transitions molecules. close proximity to the process stream, in on-line
Raman and NIR spectra contain qualitative and measurements the sample is diverted from the
quantitative information on chemical composition process and returned to the process stream, in the
and physical properties of the sample. The in-line measurements the sample is not removed
monitoring of pharmaceutical process through NIR from the process stream and can be persistent or
and Raman spectroscopy results in a huge amount non-persistent.
of spectral data. The chemo metric technique The process analyzers are more advanced, making
explains the variations in the data obtained through high time control on the quality assurance during
NIR and Raman spectroscopy. These two process the manufacturing process. The process analyzers
analyzers have the ability to supply versatile and tools must be used in a grouping with multivariate
multivariate information. The following delves the methods to eradicate the complex process
various methods of NIR and Raman spectroscopy knowledge for high time control and quality
and its effectiveness. assurance. The underlying steps or transformations
related with the help of a sensor based “process
AN OVERVIEW OF PAT TOOLS signature”. The process signatures help for process
PROCESS ANALYTICAL monitoring, control and end-point determination
TECHNOLOGY based on the level of understanding the process.
PAT is defined by the US FDA1 as a “method for The process tools, process analyzer and interface
designing, evaluating, managing and producing must be strong, dependable and have no difficulty
through timely measurements of good quality and of operation1.
performance characteristics of raw materials and
procedures with the objective of end product NEAR INFRARED SPECTROSCOPY
quality”. The objective of PAT is to be aware of the (NIR)
manufacturing process, which includes chemical, The possibility of evolution to higher excited states
physical, microbiological, and mathematical and (>v 1) is considerably lower compared to evolution
risk analysis performed in a combined method. to the first excited vibration energy state (v 1),
The current approach of US FDA1 on drug quality which is one of the advantages of NIR
is that quality cannot be examined into products spectroscopy. The NIR spectroscopy can record the
rather it should be built-in or should be by spectra without any preparation of sample while in
designed. The final products are tested on the basis the mid-infrared spectroscopy the sample is diluted
of statistical sampling and testing in order to for analysis due to the high level of absorption. The
confirm the specified standard. The quality of drug molar observation in the NIR spectroscopy is 10-
testing often requires a destructive test. The 100 times weaker than the mid-infrared
complications are higher in the end product testing spectroscopy and it is another disadvantage of NIR
as the testing is only possible after the completion spectroscopy. The radiation in the NIR region has
of batch3. The tools for PAT are characterized as higher penetration depth than the mid-infrared
multivariate tools for design, data acquisition and radiation5.
analysis, process analyzers, process control tools The infrared spectrum envelops the wavelength
and constant improvement and knowledge range from around 700 nm to 1000 µm. The term
management tools. The combination of the few infrared is referred as a wide range of wavelengths,
tools or all these tools may be applicable to a single beginning at the top end and extending to the lower
or entire manufacturing process1. wavelength used for communication at the end of
the visible spectrum6. The infrared spectrum is
PROCESS ANALYZERS classified into three parts such as far infrared (50-
Some articles4 identify that the availability of 100 µm) which are longer wavelengths, mid-
process analyzer tools have advanced from the infrared (3-50 µm) and near infrared (700-3000
tools that take univariate process measurements nm) which is contiguous to the visible spectrum.
like pH, temperature and pressure in the biological, The vibration spectroscopy relies on the notion that
physical and chemical attributes. The atom-to-atom bonds within molecules vibrate with
measurements are categorized as in-line, on-line frequencies and it is illustrated by the physics law
and at-line; in the at-line measurements the sample and is subject to calculation7. The NIR
is completely removed, separated and examined in spectroscopy is useful for qualitative and

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quantitative analysis of water, alcohol, amines and broad bands and thus result in the individual
any compounds containing C-H, N-H and O-H overlapped peaks. The NIR spectroscopy has been
groups6. The statistical methods are used in NIR proved as a powerful tool for research in
spectroscopy for interpretation in order to obtain agriculture, food, pharmaceutical, chemical,
qualitative and quantitative information from the polymer and petroleum industries8.
spectra because the NIR spectra frequently contains

Table:1 Showing the Electromagnetic Spectrum(Adapted6)

The Electromagnetic Spectrum

Designation Wavelength Range
Gamma Ray <0.05 Angstroms
X-ray 0.05-100 Angstroms
Far-Ultraviolet 10-180 nm
Near-Ultraviolet 180-350 nm
Visible 350-700 nm
Near Infrared 700-3000 nm
Middle Infrared 3-50 µm
Far Infrared 50-1000 µm
Microwave 1-300 nm
Radio Wave >300 nm

RAMAN SPECTROSCOPY laboratory analysis for the quality verification. The

The energy absorption by a molecule may leads to disadvantages of continuous process optimization;
enter a highly virtual energy state due to the persisting manufacturing difficulties and the
monochromatic light from laser source. Later, the possibility of failed batches has invited a new mode
molecule can relax back to the ground elastic state of operation to address these concerns. The mode
by producing same amount of energy that was of operation was invited by Food and Drug
taken up previously and resulted in elastic Administration (FDA) known as Process Analytical
scattering. The small parts returning to a different Technology (PAT). The PAT involves various
energy level than the incident one is called as methods and analysis in the pharmaceutical
inelastic scattering. The inelastic scattering can industry. The essentials of PAT and the
direct to a higher energy (strokes shift) or lower implementation of process analyzers and its
energy (anti-strokes shift) state of molecule based effectiveness in process monitoring are discussed.
on the incident energy state of the molecule. The Similarly, the effectiveness of NIR spectroscopy
strokes shifts are reported in the Raman than the Raman spectroscopy is analyzed.
spectroscopy because of the greater intensity. The
Raman spectroscopy is applicable as in-line and PROCESS ANALYTICAL
helps to obtain the real time data; it is frequently TECHNOLOGY
used in pharmaceutical unit operations on a As per the guidance of FDA, risk analysis is one of
molecular level9. The Raman spectroscopy has the essentials of PAT being adopted by the
expanded its application in characterizing PITs of pharmaceutical industry. The PAT identifies the
an API in final tablets and quantifying API content quality of the pharmaceutical product rather than
in tablets10.The coating variability and thickness testing the quality of the finished batch. In PAT,
are also investigated through Raman spectroscopy the variables of the critical product quality are
and it is found to be an effective method for identified from the historical data. PAT engages the
identifying fake pharmaceutical products11. use of raw material properties, manufacturing
parameters, and process monitoring and chemo
IMPLEMENTING PAT IN THE metric techniques for producing the finished
PHARMACEUTICAL INDUSTRY products of adequate quality. The vital point of
The pharmaceutical production involves the PAT is to produce the product quality information
manufacture of the finished product, pursued by in high-time. PAT helps in understanding and

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controlling the manufacturing process and the technically and organizationally, which requires co-
built-in system of PAT identifies the defects in the ordination of resources and people across various
process manufacturing rather than testing on the organizational, functional and geographic
finished products12. boundaries. The successful implementation of
The following sequential aspects are essential for process analyzer helps to save the huge amount of
the successful implementation of process analyzer investment and to improve the quality, which is
into process streams. unattainable previously. The wrong implementation
 The selection of appropriate process analyzer of analyzer leads to a loss for an organization and
or grouping of balancing process analyzer for lasts bad opinion among the people invested in the
monitoring the desired critical process and project and may get black mark on their records. It
information of product. is essential to maintain the most important factors
 The determination of process analyzer location that determine the project successful rather than
in the process stream like where and how the focusing on failure and it is important for the
process analyzer can be implemented to process analytical operator to ensure the successful
monitor the information required. implementation. The factors that increase the
 Determination of process analyzer’s optimal chance of failure of analyzer implementation is
measurement conditions in order to obtain the identified and monitored. The process analyzer
data. implementation is broadly applied to all the
 Validating the performance of the process technologies in general and can also be applied to
analyzer streams. the existing analyzer hardware. The
implementation of process analyzer involves huge
The implementation of process analyzer in the challenges, which are difficult to anticipate, and it
chemical manufacturing plant involves huge is essential for the process analyst chemist to
investment, time, effort and money. The recognize and address the challenges as early as
implementation of analyzer is very complex both possible.

Table: 2 Showing the Commonly applied PAT techniques to Pharma Unit Operations

Unit Operation or Process Step In-Line, At-Line, Off-Line Technique

Raw Materials, Dispensing NIR, Raman, Particle Size

Reaction Monitoring Mid-IR, NIR, UV-Visible
Crystallization Mid-IR, NIR, Raman, FBRM, PVM
API Drying NIR
Nanomilling NIR
Wet Granulation NIR, FBRM, PVM, Acoustics, Particle Imaging
Compounding Tank NIR, Raman, FBRM
Fluid Bed Drying NIR
Blending NIR, NIR Imaging, Raman
Lubrication NIR, LIBS
Compression NIR, Raman, NIR Imaging, LIBS, Tera-hertz, LIF
Coating NIR, LIBS, Tera-hertz
Roller Compaction NIR, Pressure Sensors, Particle Size
Hot Melt Extrusion NIR, Raman, UV/Vis, Fluorescence
Spray Drying FBRM
Packaging Reflectometry
Adjuvants Turbidity
Fermentation Mid-IR, NIR, Sensors
Freeze Drying/ Lyophilization NIR, Raman
Chemometrics Software SIMCA, Unscrambler, MATLAB
Integrated Data Network Siemens SIPAT, SynTQ, ABB xPAT, Symbion
Reference Methods HPLC, GC, Karl Fischer, LOD, Particle Size

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PROCESS ANALYZER severely in reaction to the necessity for speed in

The process analyzers are essential tools of PAT analysis and flexibility to adapt to different sample
used for real-time process monitoring and control. states. Spectrometers used to document NIR
They supply data through which significant process spectra are crucially identical with those employed
and information of product and conclusions are in other regions of electromagnetic spectrum. The
extracted. The tools predominantly obtain the equipment of NIR can incorporate a variety of
univariate process measurements like pH, devices based on the feature of sample and the
temperature and pressure to the multivariate particular analytical conditions and needs such as
information related to biological, physical and speed, sample and environmental conditions. The
chemical features of the processed materials (Ex. NIR spectroscopy is flexible compared to other
NIR and Raman spectroscopy). The process techniques.
analyzers have been mostly used for real-time
measurements of complex process and attributes of RAMAN SPECTROSCOPY
product during the pharmaceutical processing. The Raman Effect is too weak and so there is a major
NIR and Raman spectroscopic techniques permit problem in separating the Raman's effect from the
quick and non-destructive measurements without intense Rayleigh scattering. So there is a need of
preparations of sample. The implementation of using multiple filters to filter the stray light.
spectrometers with fibre optic cables helps into the Obtaining a single Raman spectrum takes a
process streams permits continuous real-time in- considerable amount of time. This slows down the
process measurements. The ability of the process planned manufacture activity which uses Raman
analyzer is to deliver versatile and multivariate spectroscopy. Raman Effect can be viewed only on
information. The process analyzers have been used solid, liquid and gas and not on metals and alloys,
in-line, at-line and on-line to monitor and control so the effect cannot be used in the manufacturing
the pharmaceutical production processes in high- process which involves metals and alloys.
time13. Identification of Raman’s effect requires heating of
The process analyzer is an essential tool within the the material by intense laser radiation; this may
PAT framework and used for the purpose of actually cause damage to the material itself. So
monitoring the Critical Process Parameters (CPPs). Raman spectroscopy cannot be used on such raw
The CPPs are identified through risk analysis and materials. A colored material absorb the laser beam
close monitoring and control is required for and emits fluorescence, this strong fluorescence
achieving the desired quality. Based on the spoils the Raman spectrum. There is difference in
criticality of the process step, it is necessary to Raman signal when it is used in single molecule
keep the process parameters within distinct and same molecule in bulk volume. Raman signal
specifications. The in-line and on-line process in single molecule is five to six times larger than
analyzer provides real-time data for exceptional the same molecule in bulk level, this makes the
control process and it results in the high quality Raman spectrum difficult to use for practical
production. purposes.

NEAR-INFRARED SPECTROSCOPY NEAR INFRARED SPECTROSCOPY VS

(NIR) RAMAN SPECTROMETER
The NIR spectroscopy has achieved broad The NIR spectroscopy has been increasingly
acceptance in different fields due to its advantages adopted in various fields as an analytical tool and
over other analytical techniques. The most salient has outdated the traditional technology. The NIR
features of NIR spectroscopy is that the ability to spectroscopy is effective and reliable than Raman
document spectra for solid and liquid samples with spectrometry because it is a non-invasive and non-
no prior manipulation. The improvements in destructive technique. It requires very minimal or
instrumentation have paved the way for sometimes no sample preparation and with the help
manufacture of spectrometers able to quickly of appropriate device the solid samples can be
provide spectra that are flexible to use in different directly measured with the help of little pre-
situations. It provides spectra quickly and forecast treatment or no pre-treatment. The measurements
physical and chemical parameters from a single and delivery of the result are very fast and the
spectrum. This instrumentation has changed remarkable developments in NIR equipments and

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chemo metrics used in conjunction with computers CONCLUSION

have facilitated the real-time extortion of PAT is a rebellion in the pharmaceutical industry
information from the samples. The automation of initiated by the United States Food and Drug
technique reduces the costs and amortization time Administration to decrease the risk of producing a
and there is no need of materials to prepare the deprived quality product and unwanted deviations
sample. The single spectrum in NIR spectroscopy associated. As PAT is the built-in technology
permits various analytics to be determined which tests the quality of the drug on the
simultaneously. The instruments of NIR are most manufacturing process rather than testing the
appropriate for the process controls at production finished product, making high time control on the
plants. The spectrometers with fibre optics present quality assurance during the manufacturing
vigorous and strong sensors for in-line, at-line and process. NIR and Raman spectroscopy are two of
on-line control process. The NIR spectroscopic the effective tools of PAT which is useful in the
results are accurate compared to the other process monitoring for the manufacturing process.
analytical techniques and their accuracy is also Though According to the research methodology
higher and sample treatment is not necessary in the NIR spectroscopy is found more effective and
NIR spectroscopy. The analytical techniques is reliable than the Raman spectroscopy as NIR
applied in various sectors like pharmaceutical, spectroscopy has been increasingly adopted in
clinical, petrochemical, agricultural food sector and various fields as an analytical tool and it is also
other miscellaneous sectors and it is found to be found more important in the manufacturing
successful in all these sectors. process. The NIR spectroscopic results are accurate
Raman spectroscopy is highly weak during the compared to other analytical technique (Raman
absence of resonance and surface development and spectrometer) used in the manufacturing process.
it is highly possible for fluorescence. The And from the research it is clear that NIR is found
possibility of the Raman effects is just about 10-6 – more competent process analyzer, which can be
10-9 per incident photon, which enforces the implemented in most of the manufacturing process
necessity for sensitive and optimized light compared to Raman. Similarly, its successful
detectors. It is possible to eliminate the implementation of process analyzer is very
fluorescence from the previously recorded Raman essential and the most important factors that
spectra using numerical methods or space resolved determine the project successful rather than
Raman spectroscopy. Typically, obtaining Raman focusing on failure and it is important for the
spectra entails shifting the sample in a step-by-step process analytical operator to ensure the successful
process until the whole region of interest is implementation.
characterized.

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