Process Analytical Chemistry (PAT) Flashcards
What is the main idea behind Process Analytical Technology (PAT)
- A system for designing, analysing and controlling in-line manufacturing process through timely measurements
- Ensuring final product quality
- Use of rapid off-line, at-line, on-line or in-line analyzers
Where does the sucess of Process Analytical Technology come from
it is related to the knowledge gained about the process and not the volume of data generated
Linking together PAT and the 12 Principles of sustainable chemistry
How can PAT effect principle 1 of preventing waste
- PAT monitoring can reduce the number of out of specification batches and impurities
- If you produce a batch of a chemical/pharmaceutical which is impure, the whole lot has to go to waste. Therefore through monitoring the reaction process, you can make everything within the specification for that product
Linking together PAT and the 12 Principles of sustainable chemistry
How can the use of PAT affect Principle number 2 - Atom Economy?
During the reaction chemistry, you can monitor the consumption if the reactants and products to:
* Prevent un-reacted materials as impurities
* Maximise yield through getting the most out of each reactant
* End the reaction when the reactants are used up and prevent degradation (hence lowering yield
Linking together PAT and the 12 Principles of sustainable chemistry
How can the use of PAT affect Principles 3-5 - Less Hazardous Synthesis, Design Benign Chemical, Benign Solvents
- Through a process called Quality By Design it can result in
- Use of less hazardous solvents
- Simpler reaction chemistry
- Safer Processes
Linking together PAT and the 12 Principles of sustainable chemistry
How can the use of PAT affect Principle number 6 - Design for Energy Efficiency?
- Using Process monitoring you can determine when a process is done and turn off the heating, agitation, and other processes
- Hence reduce energy from any addition heating which would have otherwise occured
- Reactions like: reaction chemistry, Crystallisation and form conversion, Drying and Blending
Linking together PAT and the 12 Principles of sustainable chemistry
How can the use of PAT affect Principles 8, 9 & 11 - Reduce Derivatives, Catalysis, Real-Time Analysis
- Real-Time Analysis for Pollution prevention enables:
- Reduce Derivatives and monitor catalysis to optimise reaction chemistry + minimise derivatives
- Ensure crystallisation and polymorphs are formed (especially important for pharmaceuticles)
- Avoid over-drying and degradation
- Cannot control pollutations that you cannot detect - hence minimising pollution of potentially harmful substances into the environment
What is the FDA and their guidance for pharamaceutical development?
The Federal Drug Administration of the USA
They govern the pharmaceuticles which are release
They suggest: “Quality cannot be tested into products; it should be built-in or should be by design”
What is the whole idea behind Quality by Design (QbD)
It is a framework concerned with designing and developing processes that can consistently ensure a predefined quality, resulting in real-time release of products
Why does Quality by Design require PAT
The reason we need real-time analysis, is if was not the case, the batch of product has long left the production plants with customers possibly already having consumed the product, before the issue was identified
Hence need to measure things as you are doing them to ensure everythin g is going right
What are the key benefits of Quality by design to collect data?
- Faster (real-time or near-time) measurements
- Data collected more often
- Higher precision data
- Provides the pulse of a process
Once the drug has been made, there are several steps before the product can be sold
The step have the possibility for using further PAT
Name them?
- Granulation/Drying
- Blending
- Compression
- Coating
- Packaging
What are the 4 tools associated with Process Analytical Technology?
1) Multivariate tools for design, data acquisition and analysis
2) Process analyzers
3) Process control tools
4) Continuous improvement and knowledge management tools
The PAT Tools of ‘Process Control Tool’ involves what?
- Monitoring the state of a process and actively manifpulating it to maintain a desired state
- How fast does A+B→C+D occur
- Do we see any unwanted reactions occurring
The ‘Continuous improvement and knowledge management tool’ involves what?
- Continous learning through data collection and analysis over the life cyles of a product
- Continously increasing the understanding the process but also how to make it greener
Where might you start with PAT for a chemical process?
- Often in a process it is the impurities which are most important
- Hence trying to avoid them in a chemical process is important
- Hence, you have to define very carefully what you want to measure? Why you are measuring it?
- And defining the accuracy/precision for the particular measurement etc
What things might you consider when choosing the best technique for Process Analysis?
- Must be capable of providing necessary accuracy needed for the process
- The simplest solution is best (which is the best technique for the PAT?)
- Must consider how the analyzer will interface to the process
What types of properties might be measured by a univariate sensor?
- Temperature, Pressure, Flow, Density
- pH, O₂, ion-selective electrodes
- Viscometers
- Colour, turbidity, moisture
What types of measurements would be taken by a Multivariate analyser?
- Spectroscopy based: UV-vis, IR, NIR, Raman, NMR, XRF, fluorescence
- Seperation based: mass spec, gas chromatography, HPLC
What are the benfits of spectroscopy for PAT?
- Rapid (min/sec)
- Noninvasive, noncontact, remote
- High information content
- Provides multi-faceted information (product indentification, structural information, kinetics etc)
Infrared Spectroscopy is due to….
…. vibrations, stretching and bending of bonds
different materials (+ characteric groups) absorb different wavelengths of light AND Beer-Lamberts law states that absorption is proportional to concentration
Near-IR is due to…
Other higher vibrations resulting in combination and overtone bands
In terms of Mid-Infrared Spectroscopy, what is Attenuating Total Reflectance (ATR)?
- ATR is a way of getting the light in + out of the Optical window
- There is a crystal where the light comes in and produces an effervescent wave
- This pokes slightly into the solvent, so we get a very thin samples, allowing us to measure what is going on and obtain IR information through an optic fibre
What makes Mid-IR Spectroscopy a good tool for Process Analysis due to ATR?
1) ATR overcame the issue of Water Absorption (stops the strong>3000 peak)
2) Advent of Flexible good throughput mid-IR Fibres
3) Robust instrumentation
4) Chemometric Multi-component Analyses
The attenuating total reflectance technology is placed within Probe Technology
What is the benefit of this?
- You have a probe, as shown, which is stuck into the solution and you can then produce the IR spectrum
- This is much easier than having to fill a cell and put it into the spectrometer etc
What are the advantages if Mid-IR Spectroscopy?
- Spectrum is highly structured and visually characteristic of materials
- Spectrum reflects material properties and composition
- High information content, especially for functional groups
- The data are both qualitative and quantitative (Beer-Lambert)
- Good for all sample types - solid, liquids & gases (does work better for liquids and gases however)
The plots below show two ways for the reactions of hydrogenation of Nitrobenzene to make analine
Describe how the monitoring of the processes shows the right process to be much greener?
- The process is quite solvent dependent
- Don’t want to stop the first process too soon otherwise hydroxylimine will build up which is explosive (especially in the presence of DSMO)
- However when using methanol it is a much cleaner process - nitrobenzene conc goes down and analine goes up (called x-plot)
- Can very easily be monitored through the height of the peaks
These plots again show two different ways of the hydrogenation of nitrobenzene to produce analine
The plots show the peaks in substrate/intermediates as a function of time
Why are these plots useful?
This technique (from mid-IR) is very information rich
You can monitor 3 different components at once, as well as the reaction kinetics and solution composition
Hence it results in overall great control of the reaction
What are some disadvantages of mid-IR Spectroscopy?
- Sampling can be difficult, especially for solids
- Trace measurements in aqueous media can be difficult
- Problems with windows and transfer optics - especially if you want to access reaction further away where the light doesn’t carry (overcome this using near-IR)
- Really short measuring distance (>2m) when using fibre optics
Absorption in the NIR region (780-2500nm) are generated from fundamental vibrations by two processes; overtones and combinations
What are overtones?
Overtones can be thought of as harmonic
So every fundamental will produce a species of absorptions at multipes of the frequency
Absorption in the NIR region (780-2500nm) are generated from fundamental vibrations by two processes; overtones and combinations
What are combinations?
- Combinations are more complex
- NIR absorptions are at a higher state of excitements so they require more energy than a fundamental absorption
- Combinations arise from the sharing of NIR energy between two or more fundamental absorptions
What are the advantages of NIR?
- Spectrum reflects material properties and composition
- Mainly quantitative, also used for quality control
- Good for solids (strength) and liquids
- Excellents for fiber-optic interfacing (using probes)
- non-disruptive sampling with results in seconds
What are some disadvantages of NIR Spectroscopy?
- Spectrum is not well structured and generally difficult for detailed visual characterisation (due to bands being weak)
- Generally not suitable for gases
- Aqueous systems can be difficult
- Limited mainly to OH, NH, and CH vibrations
What applications does NIR have for PAT?
- Raw material identification
- PAT for on-line or in-line process monitoring
- Tablet content uniformity and coating analysis
- Hot-melt extrusion blend consistency
- Fermentation and cell culture monitoring
Some tablets have been produced that do not appear uniformly coated and the API content variability is larger than expected
How can you verify the tablet and API uniformity without extensive, time-consuming testing?
- The use of the NIR spectrometer to perform simultaneous reflection + transmission spectroscopy
- Allows analysis of tablet coating consistency (reflection) and quantify API contnet uniformity (transmission
- Can find root cause of tablet inconsistency
How can we use NIR for rapid in-process moisture determination on a fluid bed dryer
- Once we have formed the tablet we often have to dry it (to remove water) and compress it into a tablet
- Using the first overtone, we can do a calibration for the amount of water in our material and the use this to see how long we have to put energy in to drive off the water
- NIF compares to measuring the water using more traditional methods - easily verifiable
- Overall reduced energy consumption - Principle number 6
How does Raman Spectroscopy work?
- Raman is due to light which is being scattered coming out at the same frequency (hence wavelength)
- In Stoke, the light is reflected back again, so the observation is the difference between the excited state and the ground state
- Anti-stoke uses the difference between higher and lower states as some molecules are already in the higher energy state (Boltzmann)
What are two core differences between Raman and IR
- Raman looks at symmetric modes and strong symmetric stretches
- On the other hand, IR looks at stong anti-symmetric bands (e.g. C=O)
- Raman is less sensitive to water than IR or NIR
Why can we not use Raman for quantitative analysis
Beer’s Law does not apply
Pathlength is not relevant - needs internal standard
What types of states can we sample in, within IR?
Solids, liquids, gases and slurries
Why can Raman produce a weak effect sometimes?
- There is a tradeoff between signals (blue lazer) and fluorescence (red lazer)
- With the fluorescence often interfering with dark samples
What are some benefits of Raman?
- Spectrum is highly structured and visually characteristic of material
- Reflects material properties and composition
- High information content (especially for the c-c backbone)
- good for all sample types + states
- suitable for fibre optics - hence non-invasive
What are some disadvantages of Raman Spectroscopy?
- Fluorescence interference
- Reflectance Technique - requires ratio technique for quantification
- Not as much functional group information as mid-IR
In 2004, the FDA proposed Process Analystical Technology framework strongly emphasising a shift……
….From tested-in quality after the drug product was produced
To building in quality throughout production with continuous real time quality assurance
Why is Raman particularly good at PAT for bio-pharmaceuticals?
- Allows for in-situ monitoring of purification
- cycles, buffer identification, proteins
- aggregation (important your product is not is lumps) and product identification (producing the right thing)
