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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 othertypes 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 obtainchemical information on a chemical system or process.

• Traditionally, the system or process is sampled and thesamples are transported to the analytical laboratory where

analytical procedures and instruments are used to generatedata which are then converted to chemical information bycalibrated mathematical models.

• Unfortunately, this valuable information is not used orneeded in the laboratory. Further, it is currently being

recognized that sampling errors and time delays associatedwith sample transport and analysis make it nearlyimpossible to control complex chemical processes with therequired degree of success.



PAC

• Due to increasing worldwide competition, manufacturersdesign and adapt their processes to have the highestefficiency, along with the least environmental impact.Process analytical measurement systems have played a

key role in monitoring these attributes of materialsproduction. The evolution in process analyticalmethodology has typically been characterized by takinga multifunctional laboratory technique to a hardened,

single purpose analyzer unit. The need to obtain moreinformation around the entire manufacturing process ischallenging 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 whensupported 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 chemicalproduction - petroleum, fine chemicals, commodity

chemicals, petrochemicals, biotechnology, food,

pharmaceuticals, etc. being fuelled by technological

advances in analytical chemistry together withchanging needs within the chemical industry.



• Today's business pressures require manufacturers tooptimize the availability and performance of processsystems to stay competitive. Getting higher qualityproduct out the manufacturing door has forced many

to rethink process measurement systems. Devices thatobtain analytical information from process streams arebecoming smaller and more rugged, while providingbetter connectivity to plant information and controlsystems. Advances in sensor technology, process-

sensor interface designs and data processing hardwareenable process analytical chemistry to becomesmarter, faster, and stronger.



PAC

• Traditionally, chemical engineers have relied predominantly onpressure, temperature, and flow sensors to monitor and controltheir processes.

• More recently, there have been increasing attempts to makelaboratory instruments "process hardened“ and move from "off-

line" 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 (andalso the development of noninvasive sensors for someproblematical process applications).

• Process Analytical Chemistry seeks to create new sensors andanalytical instruments that can be used as integral parts of a widerange 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 thisscene. PAC analyzers are situated either in orimmediately next to the manufacturing process.

•They are designed to withstand the rigours of amanufacturing environment and to give a highdegree of reliability. They are operated eitherautomatically or by non-technical staff such as

process operatives and produce real or near-real-time data which can be used for process controland optimization.



PAC …(5)

• The move towards PAC has been fuelled by twodevelopments. Firstly , increasing internationalcompetitiveness within the chemical industry has lead tothe widespread adoption of 'right first time' and 'just intime‘ approaches to manufacturing and quality. This has

placed the emphasis on building quality into all stages ofthe process, increased manufacturing flexibility, reducedinventory and improved control of processes.

• Secondly , during the past decade advances in analyticalchemistry and in particular the development of the

microcomputer and improved algorithms for data handling,have enabled almost instantaneous generation ofinformation.



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 ofchampions 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 inthe 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

Analysis Decision

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

high-tech equipment and typically takes several hours

(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 orminutes

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



In-line

On-line

At-line

Off-line

Design, Analysis & Control of Mfg with

measurements obtained during

processing for critical quality and

performance attributes ofraw and in process

materials to ensure final

product quality



Terminology

• Off-line analysis: This involves manualremoval of the sample, transport to themeasurement instrument which is located in a

specialized central laboratory using highlyqualified technical staff . This is typified byrelatively low sample frequency, complexsample preparation, flexible and complex

analysis. The advantages of this approacharise 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-lineanalysis-time delay, administration costs, prioritization ofwork-may be addressed by carrying out the analysis at-line.This still involves manual sampling but in this case themeasurement is carried out on a dedicated analyzer by

the process operative. At-line analysis is usuallyaccompanied by significant method development work tosimplify the sample preparation and to modify themeasurement 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 effortspent in the evaluation of what information is required tocontrol the process invariably leads to the development of amore 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 andnon-invasive analysis but we will consider all

these as one group.



On-line

Automatic sampling and analysis; process - analyzer interface



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



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 tablesummarizing these differences.



Analytical Methods• at-line: Measurement where the sample is removed,

isolated from, and analyzed in close proximity to theprocess stream, (quick testing near the process).

• on-line: Measurement where the sample is diverted fromthe manufacturing process, and may be returned to theprocess stream (investigation of partial quantitiescontinuously sampled and analyzed)

• in-line: Measurement where the sample is not removedfrom the process stream and can be invasive or noninvasive(investigation in the production flow -without sampletaking)

• Off-line – remote lab, current system (investigation ofsamples discontinuously sampled and analyzed withoutdirect –automatic- linking to the process).



ANALYTICAL MEASUREMENTS

Current manufacturing requires that tens ofthousands of analytical measurements are requiredat 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 areaand 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 differentsamples and load them into the instrument thenpress 1 external button and the At-line Analyser

would perform a different test or a differentcombination of tests on each sample and exportthe results automatically.



On-line analysers are fully automated systemsused to closely monitor (1-12 results per hour)the concentrations of analytes that are critical tothe production process. On-line analysers are

able to control external devices such as pump orvalves as part of their analysis sequence and asthe results are exported automatically theanalyser can also control external devices based

on their analysis results eg turning on/off dosingpumps. The Analysers can be operated remotelyvia 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 processanalysis

• The only limitation is the cost and time involved inmaking technology safe and robust.

• PAC has its origins in the Petrochemicals andPetroleum industry with large-scale continuousprocesses where extreme pressures on unitproduction costs required the development of on-

line analyzers for control and feedback.• This led to the development of physical property

analyzers and the implementation of on-line gaschromatographs 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 levelof 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 recipefor disaster. There is an ongoing

need for a high level of technical

involvement.



• Process analytical chemistry has been performed in thepetrochemical industry for several decades. Some of theearliest univariate tools such as pH meters, oxygen sensors,

• Along with these, there are many more tools availableincluding on-line chromatography, spectroscopy (NIR, mid-

infrared, mass spectroscopy, nuclear magnetic resonancespectroscopy, and others), viscosity measurements, and X-ray analysis and flow meters are still in use today.

• Savings on implementation of real-time analysis can comefrom the better use of raw material, less energy

consumption, higher throughput or any combination of theabove.



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 thestrategy work properly.



Potentials of PAC

Product

• Improve product

quality

• Improve efficiency

and manage

variability• Reduce production

cycle times

• Prevent rejects,

scrap, and re-

processing

• Improve process

understanding

PAC Process streamRaw material

Environment

Raw material

• Improve raw

material quality

• Manage variability

• Improve consistency

and grading• Improve utility of raw

materials

• Improve

processing quality

Environmental footprint

• Improve energy, water and material use

• Increase capacity

• Optimize cleaning procedures

M d l



Modern process analyzers or process

analytical chemistry tools

• Process analytical chemistry as a discipline has grownsignificantly during the past several decades, due to anincreasing appreciation for the value of collectingprocess data during production.

•

From the simple process measurements such as pH,temperature, and pressure, modern tools that measurechemical composition and physical attributes haveevolved.

• These modern process analysis tools provide

nondestructive measurements that containinformation related to both physical and chemicalattributes of the materials being processed.

M d l



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 tothe manufacturing process

• on-line where measurement system is connected to theprocess via a diverted sample stream; the sample may bereturned 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) inthe processor, the process stream is not disturbed



Profile of a Process Analytical Scientist

• Technical-

• Interpersonal effectiveness-

• Initiative-

• Business focus-

• Innovative-

•

Learning• Overall leadership



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.

EVOLUTION OF PACPAT



Comparison of analytical strategies for process

monitoring.

PROCESS ANALYTICAL TECHNOLOGY



PROCESS ANALYTICAL TECHNOLOGY

PAT TOOLS:

On-line real-time monitoring (spect roscopy )

Real-time multivariate data analysis (chemometr ics )

Process dynamics and control

“A set scientific

principles and tools

for supporting

innovation in

production”



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 processmaterials & 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) ofcritical quality and performance attributes of

raw and in-process materials and processes,

with the goal of ensuring final productquality”.



Process Analytical Technology

Enhedens navn

© Engelsen & Newlin



PAT• The term Process Analytical Technology (PAT) was introduced by the US

FDA as an initiative to bring an improved understanding of pharmaceuticalmanufacturing 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 ofempirical 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 thatbiopharmaceuticals 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 RawMaterials.



PAT

Process Engineering Regulatory Reform

Process Analytical

Chemistry Manufacturing

Science

PAT

Need for PAT for Advanced



Need for PAT for Advanced

Manufacturing Control



The different unit operations that comprise a typical pharmaceuticalprocess. 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 with analytical

chromatography for on-line monitoring of a harvest process



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

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



d



Need

l f



Principles of PAT

• Quality cannot be tested

into final; it should be built

– in, or should be by design

h i h l f ?



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?



WHAT WILL PAT MEAN?

H PAT k ??



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

T f PAT I l i



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

h l b h b l



Why PAT Analysis is better than Lab. Analysis

• Control environment-

• Speed-

• Operator error-

• Safety-

• Sample integrity

A li ti



Applications

Process Steps PAT Tech. in-line, off-lineTesting

Raw material, Dispensing NIR, Raman

Reaction monitoring Mid – IR, N-IR, UV-Visible

Crystallization Mid - IR, RamanAPI drying N - IR

Wet granulation N - IR

Fluid bed drying N - IR

Blending N – IR, Raman

Lubrication N - IR

Coating N - IR

Ad t



Advantages

• Reduction in production cycle time-• Preventing reprocessing & rejection-

• Increase automation-

• Improve operator safety-

• Reduce human error-

• Improving energy & material use & increase capacity-

• Continuous process-

• Controlling variability-• Continuous improvement & knowledge management-

Di d t



Disadvantages

• Require efforts during design-

• Implementation & maintenance stages is high-

• Require specialized, expertise person-

• Costly-

PROCESS ANALYSER



PROCESS ANALYSER

PROCESS ANALYSIS AND CONTROL:



HOW TO EFFECTIVELY IMPLEMENT

AT LINE ANALYSIS SAMPLING



AT-LINE ANALYSIS: SAMPLING

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



( )

NIR FOR IDENTIFY



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



( )

RAPID ASSAY FOR REAL TIME RELEASE

ON LINE ANALYSIS SAMPLING



ON-LINE ANALYSIS - SAMPLING

ON-LINE ANALYSIS: MICROWAVE-



MICROWAVE FOR WATER CONTENT

ON LINE ANALYSIS: UV UV FOR CIP



ON-LINE ANALYSIS: UV – UV FOR CIP

IN LINE ANALYSIS SAMPLING



IN-LINE ANALYSIS-SAMPLING

IN-LINE ANALYSIS: NIR –



FLUID BED DRYING - NIR

SUMMARY



SUMMARY

pat-bahan kuliah 2016

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