Process Analytical

Technology (PAT)
QBD – Quality By Design
In a QBD approach to manufacturing a pharmaceutical product, the quality of the product is of prime consideration rather
than simply testing the product for quality towards to the end. In practice, this means identifying the sources of variability
that could possibly affect a process.
QTPP – Quality Target Product Profile
QTPP is a summary of the quality characteristics of a pharmaceutical product. These quality characteristics are essential to
ensure the finished product meets the required standard of quality.
CQA – Critical Quality Attributes
The FDA says CQAs apply to any “physical, chemical, biological, or microbiological property or characteristic” that must be
within a limit or range to ensure the pharmaceutical product meets the required quality standard. Eg. Effect of Ph on rate
of release.
CPP – Critical Process Parameters
A CPP is a variable that can impact the CQA. Therefore, CPPs must be monitored to enable early and accurate detection of
deviations outside acceptable limits that will impact product quality. CPPs include temperature, pH, cooling rate, rotation
speed, etc.
CMA (Critical material Attributes): relates to input materials and their properties.
PAT – Process Analytical Technology
PAT refers to a method or system of testing
What is “PAT” ???
■ PAT has been defined as “a system for designing, analysing, and controlling manufacturing through
timely measurements (i.e., during processing) of critical quality and performance attributes of raw and
in-process materials and processes, with the goal of ensuring final product quality”

PAT was originally introduced by the US FDA and later adopted by the International Council for
Harmonisation.
The PAT Guidance turned out to be the first of a collection of guidelines that we today refer to as the
‘science and risk based guidelines’ or ‘the QbD guidelines’. These includes the ICH Q8(R2) and Q11 .

Principle
Quality cannot be tested into products; it should be built-in or should be by design.

The definition refers to ‘timely measurements (i.e. during processing) of critical quality and
performance attributes’, meaning measurements of the finished product critical quality attributes
(CQAs), intermediate CQAs or raw material CQAs, that is, measurements of attributes of critical materials

PAT is a system, not an analyser, that requires action to be taken based on real‐time information.
Goals of PAT
 Identify the defects in process manufacturing
 Reduce process variation
 Enhance process safety
 Produce product quality information in high time
 Building quality into products
 Enhance understanding and control of manufacturing process

PAT framework
A. Process Understanding B. Principles and Tools

A.Process Understanding
1. All critical sources of variability are identified
2. Variability is managed by the process
3. Product quality attributes can be accurately and reliably predicted over the design space established
4. Reduce burden for validating systems - provide more options for justifying and qualifying systems
intended to monitor and control attributes
B. PAT Tools
The tools of PAT can, during development, facilitate the identification of CPPs and relevant
material CQAs, identification of interactions between process parameters, attributes and
product CQAs, for establishing the design space, the related control strategy, scale‐up,
technology transfer and product and process specifications.
a. Multivariate Tools for Design, Data Acquisition and Analysis
■ Use of multivariate mathematical approaches - statistical design of experiments, response surface methodologies,
process simulation, and pattern recognition tools.
■ Methodological experiments - statistical principles, reference distribution, randomization - effective means for
identifying and studying effect and interaction of product and process variables
■ Identification and evaluation of critical performance parameters
■ Identification of failure modes and mechanisms and quantify their effects on product quality

b. Process Analysers
Process analysers may be operated in different modes:
Off‐ line: A sample is taken from the process and analysed in a laboratory. It may take several days to get the
results.
At‐line: A sample is taken from the process and analysed in close proximity. It usually takes minutes to get the
results.
On‐line: Part of the process stream is diverted from the main process and analysed without interruption. A sample
might be collected for reference purpose or the analysed sample returned to the process stream. It usually takes
seconds.
In‐line: A process analyser is located within the process stream in a non ‐invasive way. This could, as an example,
be a measurement through a measuring head (probe) connected directly to a process equipment window (e.g. a
blender).
 Measurements collected - need not be absolute values
■ Measurement of relative differences in materials before and during processing - provide useful information for
process control.
■ Install process analysers – on existing equipment – done after risk analysis – ensures the installation does not
adversely affect process and product quality.

c. Process Control Tools

■ Strategies - intended to monitor state of a process and actively manipulate it to maintain a desired state.
■ Strategies should accommodate - attributes of input materials
ability and reliability of process analysers
the achievement of process end points

Design and optimization of drug formulations and manufacturing processes within PAT Framework can include
the following steps:
d. Continuous Improvement and Knowledge Management
 Integration of PAT – large volume of data generated – converted to knowledge
 Knowledge management tools – way to store data – use models, process simulation and process recognition
tools – develop process knowledge and understanding
 Information summarised in electronic batch record or external repository - centralizes data and process
instructions
 Data can be verified by QA
 Computerised controls can be built into electronic batch records – ensures quality is not compromised – reduces
risk of product recalls

2. Risk-Based Approach
■ Level of process understanding - inverse relationship - risk of producing a poor quality product.
■ Well understood processes - opportunities - less restrictive regulatory approaches
■ Focus on process understanding - facilitate risk-based regulatory decisions and innovation
3. Integrated Systems Approach
■ Necessary – evaluating and timely application of efficient tools – satisfy patient and industry
needs
■ Advances occurred/anticipated to occur – brings development, manufacturing, quality assurance
and information/knowledge managements functions closely together – coordinated in integrated
manner
■ Upper management support – critical – successful implementation

4. Real Time Release

■ Ability to evaluate and ensure – acceptable quality of in-process and/or final product – based on
process data
■ PAT component – valid combination of assessed material attributes and process controls –
assessed using direct/indirect process analytical methods
■ Comparable to alternative analytical procedures – final product release
 Typical attribute measurements by process
sensors
Process sensor In‐process OR
Intermediate CQA
Application

pH in‐line pH pH sensors are widely used in

aqueous processes.
Conductivity in‐line Purity Measurement on total ionic concentrations (e.g. dissolved compounds) in aqueous
chemical and biologics processes. Widely used applications are water and product
purification, cleaning in place (CIP)/SIP (clean in place/ steam in place) control

Capacitance in‐line Viable Cell Density Bioreactor, cell growth

Total organic carbon (TOC) TOC Measurement of ppb‐level of organic contamination using UV oxidation
and conductivity measurement technology. Used for water purification processes.
Refractive index (RI) Concentration of dissolved Measurements based on refracted and reflected light Used, e.g. for feed control in
solids in a liquid (or liquid a bioreactor
mixtures)

Dissolved oxygen sensor DO Bioreactor, fermentation processes

Dissolved carbon dioxide CO2 Fermentation processes

sensor

Turbidity analysers Colour, cloudiness Bioreactors

Benefits of PAT
■ Greater flexibility in process design;
■ Reduction in costs and an improvement in yield;
■ Reduction or elimination of end-product testing with an impact on release;
■ Simplification of the initial and ongoing process validation;
■ Simplified implementation of changes to starting materials.
Infrared (IR): Absorption in the IR or mid‐infrared (MIR) region (2.5–50 µm or wavenumber: 4000–200 cm-1)
gives structural information about a compound.
One of the advantages of IR is that it can provide a snapshot or even a video of the process in real time without
requiring multivariate modelling.
IR has found a niche in Active Pharmaceutical Ingredient (API) development
FTIR‐ATR (Fourier Transform Infrared ‐ Attenuated Total Reflection) is a well‐established standard method used to
study drug release in semi‐solid formulations, drug penetration and the influence of penetration modifiers.

Near Infrared (NIR): applicable to liquids, powders and solids. The NIR region of the electromagnetic spectrum covers
750 nm to 2500 nm (wavenumbers: 13,300 to 4000 cm -1).
NIR spectra provide information on overtones and combinations of fundamental vibrations.

Advantages of using NIR:

● The absorption is 10–100 times weaker than in IR (mid ‐infrared) resulting in deeper material penetration.
● High NIR throughput is possible, even when employing low ‐cost fibre optics.
● NIR light penetrates PE (polyethylene) materials and glass, making non ‐invasive analysis possible.
● Low‐cost instruments with high signal‐to‐noise ratio (SNR).
● Endpoint determination is possible, for example, reaction, drying, granulation, blending and coating.
● Material characterisation is possible, for example, identity, polymorphs, moisture content, bulk density,
homogeneity and concentration.
● Robust industrial designs possible.
Tunable Diode Laser Spectroscopy (TDLS)
An NIR diode laser tunable, in a very narrow wavelength region, can be used for measuring several physical or
chemical analytes.

Ultraviolet‐Visible (UV‐Vis)
UV‐Vis is another spectral technique that can be used to study how radiation interacts with samples. UV ‐Vis
spectroscopy is used for quantitative analysis of solution concentrations where straightforward detection is
needed

Raman
Raman spectroscopy is used for routine qualitative and quantitative measurements of both inorganic and organic
materials, and it is successfully employed to solve complex analytical problems such as determining chemical
structures and polymorphic identity. Gases, vapours, aerosols, liquids and solids can be analysed. It does not
detect water, making it attractive for analysing aqueous solutions.

Particle Vision and Measurement (PVM)

A probe‐based video microscope can be used to gain an understanding of particle characteristics such as
morphology, shape, size and surface area.

X‐Ray Fluorescence (XRF)

XRF is an elemental, non‐destructive technique. Liquids, semi‐solids and solids can be analysed in situ, making the
technique simple but highly sample dependent. XRF is normally used when there is a specific element of interest .
Typical attribute measurements by process analysers
PAT applications used during processing in lieu of conventional end‐product QC testing
Elements to consider for inclusion in a PAT application, whether it is for gaining
process understanding or for process control.
THANK
YOU