Kimia Analitik Proses

Process Analytical Chemistry (PAC)

Haryadi

Introduction

Traditional methods for controlling chemical manufacturing processes have relied exclusively on the
measurement of temperature, pressure and flow rate.
Only when more information was essential for the safe operation of a plant would the addition of other
types of process analyzers be considered.
More recently, the manufacture of new polymers, materials and other complex products has demanded
more timely composition data in order to ensure that the highest possible quality product be made at the
lowest possible cost.
Better process control with the use of detailed, real-time chemical measurements has become the key to
lowering quality costs, i.e. costs associated with reprocessing, destroying or selling off-spec material.
Quality costs in chemical and materials manufacturing are estimated to be ten per cent of sales!
Sophisticated on-line and in-line chemical analyses are also required when it is necessary to determine not
only product composition, but also product performance during manufacturing.
For example, octane numbers for gasoline, and several other performance parameters for all fuels, are
today determined on-line during blending from near infrared spectral data analyzed by multivariate
calibration methods.
Another application involves spectral data acquired during polymerization processes to predict quality
parameters such as hardness, elongation or dye ability of the polymer product.
Finally, recent environmental regulations require data on aspects such as impurities, solvents and
wastewater, to ensure that chemical manufacturing is safe for workers, for communities near chemical
plants, and for the environment. These demands for real-time quantitative chemical information on a
growing list of manufacturing processes present new challenges to analytical chemists, instrument
engineers and plant supervisors.

PROCESS ANALYTICAL CHEMISTRY (PAC)

Chemical analysis can be thought of as a means to obtain
chemical information on a chemical system or process.
Traditionally, the system or process is sampled and the
samples are transported to the analytical laboratory where
analytical procedures and instruments are used to generate
data which are then converted to chemical information by
calibrated mathematical models.
Unfortunately, this valuable information is not used or
needed in the laboratory. Further, it is currently being
recognized that sampling errors and time delays associated
with sample transport and analysis make it nearly
impossible to control complex chemical processes with the
required degree of success.

PAC
Due to increasing worldwide competition, manufacturers
design and adapt their processes to have the highest
efficiency, along with the least environmental impact.
Process analytical measurement systems have played a
key role in monitoring these attributes of materials
production. The evolution in process analytical
methodology has typically been characterized by taking
a multifunctional laboratory technique to a hardened,
single purpose analyzer unit. The need to obtain more
information around the entire manufacturing process is
challenging this paradigm.

Process Analytical Chemistry (PAC)

PAC is a branch of Analytical Chemistry dedicated to
obtaining real time quantitative and qualitative
information about a chemical process.

to monitor and control a process

efficient use of energy, time and raw material

Callis, Illman, Kowalsky. Process Analytical Chemistry. Analytical Chemistry. Vol 59(9). 1987

PAC(1)
Process Analytical Chemistry (PAC) is the application of
analytical science to the monitoring and control of industrial
chemical process.
This information may be used to both control and optimize
the performance of a chemical process in terms of capacity,
quality, cost, consistency and waste reduction.
PAC encompasses a combination of analytical chemistry,
process engineering, process chemistry, and multivariate data
analysis. It is a multidisciplinary field that works best when
supported by a cross-functional team including members
from manufacturing, analytical chemistry, and plant
maintenance.

PAC(2)
PAC is not new. It has been applied in the petroleum
and petrochemical industries since the 1950s but is
presently going through a reincarnation and is a
rapidly developing field in all areas of chemical
production - petroleum, fine chemicals, commodity
chemicals, petrochemicals, biotechnology, food,
pharmaceuticals, etc. being fuelled by technological
advances in analytical chemistry together with
changing needs within the chemical industry.

 Today's business pressures require manufacturers to

optimize the availability and performance of process
systems to stay competitive. Getting higher quality
product out the manufacturing door has forced many
to rethink process measurement systems. Devices that
obtain analytical information from process streams are
becoming smaller and more rugged, while providing
better connectivity to plant information and control
systems. Advances in sensor technology, processsensor interface designs and data processing hardware
enable process analytical chemistry to become
smarter, faster, and stronger.

PAC
Traditionally, chemical engineers have relied predominantly on
pressure, temperature, and flow sensors to monitor and control
their processes.
More recently, there have been increasing attempts to make
laboratory instruments "process hardened and move from "offline" to "at-line" analysis.
In addition, there has been a growing demand for the development
of novel sensors to allow for true "on-line" analysis and control (and
also the development of noninvasive sensors for some
problematical process applications).
Process Analytical Chemistry seeks to create new sensors and
analytical instruments that can be used as integral parts of a wide
range of chemical processes for process monitoring and control.

PAC(3)
In a traditional chemical manufacturing plant, samples are taken from
reaction areas and transported to the analytical laboratory which is
typically centralized. In PAC the samples are analyzed by highly qualified
technical staff using state-of-the-art equipment producing results typically
in a few hours to a few days.
Such analysis is generally used retrospectively to measure process
efficiency, to identify materials which need to be reworked or discarded or
in a multistage batch synthesis to assess the charge for the next stage.
Where these results are critical to the continuation of the process, the
process is usually designed to accommodate this time delay giving rise to
longer cycle times and reduced plant utilization.
Process control in this environment is effected by an experimental
correlation of physical parameters during the process such as flow rates,
times, temperatures, pressures with chemical composition, quality and
yield of the derived material followed by subsequent control of these
physical parameters.

PAC (4)
Implementation of PAC dramatically changes this
scene. PAC analyzers are situated either in or
immediately next to the manufacturing process.
They are designed to withstand the rigours of a
manufacturing environment and to give a high
degree of reliability. They are operated either
automatically or by non-technical staff such as
process operatives and produce real or near-realtime data which can be used for process control
and optimization.

PAC (5)
The move towards PAC has been fuelled by two
developments.
Firstly,
increasing
international
competitiveness within the chemical industry has lead to
the widespread adoption of 'right first time' and 'just in
time approaches to manufacturing and quality. This has
placed the emphasis on building quality into all stages of
the process, increased manufacturing flexibility, reduced
inventory and improved control of processes.
Secondly, during the past decade advances in analytical
chemistry and in particular the development of the
microcomputer and improved algorithms for data handling,
have enabled almost instantaneous generation of
information.

PAC (6)
Moving from a traditional analysis approach to a PAC approach is not
easy, not only does it require significant technical developments but
it also requires a 'cultural' change.
This change needs to be embraced not only by the analyst
community, but also by manufacturing, R&D and engineering, etc.
This change process requires a 'champion' or better still a number of
champions at both the managerial and technical levels in order to be
successful.
The use of PAC enables one to gain a deeper understanding of the
process. This in turn can lead to more consistent product, reduced
waste, improved manufacturing efficiencies, overall improvement in
the use of resources, improved safety, and the reduced costs that can
be garnered from each of these.

Key differences between traditional approaches and PAC

approach toward Process

Sample

Transport

Sample

Analysis

Communicate

Decision

(a) Traditional approach to process control. Analysis employs technical staff,

high-tech equipment and typically takes several hours
Analysis

Decision

(b) Process analytical chemistry approach to process control. Analysis is either automatic or
employs non-technical staff, utilizes rugged and reliable equipment and takes seconds or
minutes

Better control is the prime goal as it will improve product quality, result in less
waste, increase the safety of operations, and thus increase profitability.

Process Monitoring

Design, Analysis & Control of Mfg with

measurements obtained during
processing for critical quality and
In-line
performance attributes of
raw and in process
On-line materials to ensure final
product quality

Off-line
At-line

Terminology
Off-line analysis: This involves manual
removal of the sample, transport to the
measurement instrument which is located in a
specialized central laboratory using highly
qualified technical staff. This is typified by
relatively low sample frequency, complex
sample preparation, flexible and complex
analysis. The advantages of this approach
arise from the economy of sharing expensive
instruments and skilled staff.

Off-line

Manual sampling and analysis at a separate laboratory

Terminology(1)
At-line analysis: Many of the deficiencies of off-line
analysis-time delay, administration costs, prioritization of
work-may be addressed by carrying out the analysis at-line.
This still involves manual sampling but in this case the
measurement is carried out on a dedicated analyzer by
the process operative. At-line analysis is usually
accompanied by significant method development work to
simplify the sample preparation and to modify the
measurement technique to permit the use of robust,
reliable instrumentation. [It is a mistake to simply transfer
the laboratory analysis to the plant floor - time and effort
spent in the evaluation of what information is required to
control the process invariably leads to the development of a
more robust solution.]

At-line

Manual sampling and analysis at the process

Terminology (2)
On-line analysis: We use this definition to
describe all examples of fully automated
analyzer systems. Other authors have
subdivided this further into on-line, in-line and
non-invasive analysis but we will consider all
these as one group.

On-line

Automatic sampling and analysis; process - analyzer interface

On-line analysis
True on-line

In-line

Non-invasive

Some of the process

liquors are passed
through an on-line
analyser
No sampling; analyser
probe inserted into
reactor or pipe
No sampling; no direct
contact required between
process liquors and
analyser

In -situ: sensor inside bioreactor

Ex-situ: sample transferred to external device for analysis

TRADITIONAL FACILITY

Traditional Manufacturing Approach

21st CENTURY CONCEPT

Manufacturing Approach with PAT-PAC

FACILITIES OPERATING WITH PAT-PAC

OPERATIONAL COSTS

PAC

 What are the differences between In-line,

On-line, At-line and Off-line Analysers.
When it comes to performing routine testing
of process samples there are 4 basic options
of instrumentation, Inline, On-line, At-line and
Off-line(laboratory). Please find following a
brief description of each of these and a table
summarizing these differences.

Analytical Methods
at-line: Measurement where the sample is removed,
isolated from, and analyzed in close proximity to the
process stream, (quick testing near the process).
on-line: Measurement where the sample is diverted from
the manufacturing process, and may be returned to the
process stream (investigation of partial quantities
continuously sampled and analyzed)
in-line: Measurement where the sample is not removed
from the process stream and can be invasive or noninvasive
(investigation in the production flow -without sample
taking)
Off-line remote lab, current system (investigation of
samples discontinuously sampled and analyzed without
direct automatic- linking to the process).

ANALYTICAL MEASUREMENTS
Current manufacturing requires that tens of
thousands of analytical measurements are required
at a manufacturing facility annually
- These typically take place for several reasons
QC testing for batch release
In process testing to reduce risk
Raw material acceptance testing
- Analytical Development
Develop tests to be finally used in the facility
Support drug development process

Analytical Methods
In-Line
In-line analysers are simple probes or measuring devices that
are placed directly into a process stream. They are used to
measure such things as pH, temperature, pressure, density
and flow.
Off-Line
Off-line Analysers are laboratory instruments designed to be
in an environmentally controlled location and used by
technically trained personal. They offer the greatest versatility
of analysis methods but require the most man hours to
perform an analysis and input the results ie they have the
longest results turn around time. Laboratory instruments are
used when there is a large variety of test methods required
and the result turn around time is not critical.

 At-line
An At-line Analyser, sits in the production area
and is used by an Operator. It is configured to
perform a series of tests on a variety of samples.
For instance an Operator could collect 4 different
samples and load them into the instrument then
press 1 external button and the At-line Analyser
would perform a different test or a different
combination of tests on each sample and export
the results automatically.

 On-line analysers are fully automated systems

used to closely monitor (1-12 results per hour)
the concentrations of analytes that are critical to
the production process. On-line analysers are
able to control external devices such as pump or
valves as part of their analysis sequence and as
the results are exported automatically the
analyser can also control external devices based
on their analysis results eg turning on/off dosing
pumps. The Analysers can be operated remotely
via a modem.

On-line analysers
Several steps and functions:
They can perform a variety of
pre-treatments on the sample
before analysis such as;
Filtration.
Cooling
Pressure reduction
Heat tracing.
Digestion with acid, heat
and/or UV.
Dilution

Precipitation
Degassing
Homogenizing
Flow metering
Phase separation

GENERAL ANALYSIS TIME

The effect of locating an analytical device with respect to the object on the time delay
in obtaining analytical information.

Characteristics of test kit, the speed of analysis complexity and sensitivity

of equipment

Technology and instrumentation

All laboratory techniques can be applied to process
analysis
The only limitation is the cost and time involved in
making technology safe and robust.
PAC has its origins in the Petrochemicals and
Petroleum industry with large-scale continuous
processes where extreme pressures on unit
production costs required the development of online analyzers for control and feedback.
This led to the development of physical property
analyzers and the implementation of on-line gas
chromatographs and mass spectrophotometers.

The activities required for the success of a

process analysis solution

The activities required for the

success of a process analysis
solution are outlined in Figure.
Steps 2-6 are the project phase
usually led by a technical function
and assuming an appropriate level
of technical competence are usually
carried out successfully. In many
organizations, the involvement of
the technical functions ends here
and the system is 'handed over' to
production. This is usually a recipe
for disaster. There is an ongoing
need for a high level of technical
involvement.

 Process analytical chemistry has been performed in the

petrochemical industry for several decades. Some of the
earliest univariate tools such as pH meters, oxygen sensors,
Along with these, there are many more tools available
including on-line chromatography, spectroscopy (NIR, midinfrared, mass spectroscopy, nuclear magnetic resonance
spectroscopy, and others), viscosity measurements, and Xray analysis and flow meters are still in use today.
Savings on implementation of real-time analysis can come
from the better use of raw material, less energy
consumption, higher throughput or any combination of the
above.

Advantage and Disadvantage

Fundamental technologies of Process

Analytical Chemistry (PAC).
Understanding
why
the
centralized laboratory strategy
is still around, one must
understand that the process
analytical strategy by no
means can be considered
trivial. Several key strategies
must be mastered to make the
strategy work properly.

Potentials of PAC
Raw material
Improve raw

material quality
Manage variability
Improve consistency
and grading
Improve utility of raw
materials
Improve
processing quality

Product
Raw material

PAC

Process stream

Environment

Environmental footprint
Improve energy, water and material use

Increase capacity
Optimize cleaning procedures

Improve product

quality
Improve efficiency
and manage
variability
Reduce production
cycle times
Prevent rejects,
scrap, and reprocessing
Improve process
understanding

Modern process analyzers or process

analytical chemistry tools
Process analytical chemistry as a discipline has grown
significantly during the past several decades, due to an
increasing appreciation for the value of collecting
process data during production.
From the simple process measurements such as pH,
temperature, and pressure, modern tools that measure
chemical composition and physical attributes have
evolved.
These modern process analysis tools provide
nondestructive measurements that contain
information related to both physical and chemical
attributes of the materials being processed.

Modern process analyzers or process

analytical chemistry tools
These measurements can be performed in the following
manner:
off-line in a laboratory
at-line in the production area, during production close to
the manufacturing process
on-line where measurement system is connected to the
process via a diverted sample stream; the sample may be
returned to the process stream after measurement
in-line where process stream may be disturbed (e.g., probe
insertion), and measurement is done in real time
noninvasive, when the sensor is not in contact with the
material (e.g., Raman spectroscopy through a window) in
the processor, the process stream is not disturbed

Profile of a Process Analytical Scientist

TechnicalInterpersonal effectivenessInitiativeBusiness focusInnovativeLearning

Overall leadership

EVOLUTION OF PAC PAT

Process measurement systems have evolved from sequential packages to interdependent functions.
In the former case, functions were inputs to the next step in the measurement procedure; in the
latter case, functions work together to produce an accurate description of the state of the
manufacturing process.

Comparison of analytical strategies for process

monitoring.

PROCESS ANALYTICAL TECHNOLOGY

A set scientific
principles and tools
for supporting
innovation in
production

PAT TOOLS:
On-line real-time monitoring (spectroscopy)
Real-time multivariate data analysis (chemometrics)

Process dynamics and control

What is PAT
A system for designing, analyzing & controlling
manufacturing through timely measurements
(i.e. during processing) of critical quality &
performance attributes for raw & in process
materials & processes with the goal of
ensuring final product quality

PAT
Process analytical technology (PAT) can be
defined as a system for designing, analyzing,
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.

Process Analytical Technology

Engelsen & Newlin

Enhedens navn

PAT
The term Process Analytical Technology (PAT) was introduced by the US
FDA as an initiative to bring an improved understanding of pharmaceutical
manufacturing processes to increase the quality of their products.
The FDA uses the expression to build in quality into the pharmaceutical
manufacturing process, thereby implying that high product quality
should ideally be created already at the design stage of the manufacturing
process contrary to traditional processes that are often the result of
empirical or rule-of-thumb design.
In addition, they also emphasize on the need for improved on-line
monitoring and control methods to maintain high product quality during
manufacturing operations and control. In the biopharmaceutical industry
PAT principles are adopted with more care due to the fact that
biopharmaceuticals and their production systems are very complex and
crucial.

PAT & QbD in the Manufacturing Process

Raw
Material
Range

Process
Monitoring
& Control

Final Product

Variation in Raw Materials is expected and understood.

Process Provides a Design Space or Boundaries for Raw
Materials.

PAT
Process Engineering

Regulatory Reform

PAT

Process Analytical
Chemistry

Manufacturing
Science

Need for PAT for Advanced

Manufacturing Control

The different unit operations that comprise a typical pharmaceutical

process. Each step can potentially benefit from implementation of one
or more PAT applications. Copyright permission from Advanstar
Communications. PSD: Particle size distribution; T: Temperature; DW:
Dry weight; PI: Product impurity

Use of an ultrafiltration membrane in combination

chromatography for on-line monitoring of a harvest process

with

analytical

On-line monitoring, by NIR spectroscopy, of moisture content

(both unbound and bound water) during freeze drying in vials

Need

Principles of PAT

Quality cannot be tested

into final; it should be built
in, or should be by design

What is the goal of PAT?

Building quality into products
To enhance understanding and control the
manufacturing process
The goal is to reduce variation in our process
To enhance process safety

WHAT WILL PAT MEAN?

How PAT works ??

Selection of Process

Selection of Suitable PAT System

Identification of CPP (critical process parameters

Design Process

On-line Test

In-line Test

Types of PAT Implementation

Initial phase Process Optimization
Scale-up phase Comparing data
Temporary process gaining process info &
understanding process
Permanent process Actual process
monitoring & control

Why PAT Analysis is better than Lab. Analysis

Control environmentSpeedOperator errorSafetySample integrity

Applications
Process Steps
Raw material, Dispensing
Reaction monitoring

PAT Tech. in-line, off-line

Testing
NIR, Raman
Mid IR, N-IR, UV-Visible

Crystallization
API drying
Wet granulation
Fluid bed drying
Blending
Lubrication
Coating

Mid - IR, Raman

N - IR
N - IR
N - IR
N IR, Raman
N - IR
N - IR

Advantages

Reduction in production cycle timePreventing reprocessing & rejectionIncrease automationImprove operator safetyReduce human errorImproving energy & material use & increase capacityContinuous processControlling variabilityContinuous improvement & knowledge management-

Disadvantages

Require efforts during designImplementation & maintenance stages is highRequire specialized, expertise personCostly-

PROCESS ANALYSER

PROCESS ANALYSIS AND CONTROL:

HOW TO EFFECTIVELY IMPLEMENT

AT-LINE ANALYSIS: SAMPLING

AT-LINE ANALYSIS: NEAR INFRA-RED(NIR)

NIR FOR IDENTIFY

AT-LINE ANALYSIS: RAMAN SPECTROSCOPYRAMAN FOR IDENTIFY

AT-LINE ANALYSIS: X-RAY FLORESCNCE (XRF)

RAPID ASSAY FOR REAL TIME RELEASE

ON-LINE ANALYSIS - SAMPLING

ON-LINE ANALYSIS: MICROWAVEMICROWAVE FOR WATER CONTENT

ON-LINE ANALYSIS: UV UV FOR CIP

IN-LINE ANALYSIS-SAMPLING

IN-LINE ANALYSIS: NIR

FLUID BED DRYING - NIR

SUMMARY