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Near Infrared Spectroscopy Near Infrared Spectroscopy Applications in Applications in
Pharmaceutical IndustryPharmaceutical Industry
เภสัชกรนิติ สันแสนดีNiti Sunsandee
Pharmacist
NIR Applications in NIR Applications in Pharmaceutical IndustryPharmaceutical Industry
Overview• Principle and Application• Regulatory requirements• How to start with NIR• Raw material analysis by NIR• Quantitative NIR Applications• Process Analytical Technology
activities• Summary
Wavenumber [cm-1]
Energy [J]
Spectroscopy is the study of the interaction between matter and electromagnetic radiation
Near Infrared Spectroscopy (NIR) is a type of vibrational spectroscopy
NIR MIR FIRVisible Microwave
Wavelength [nm]
The Electromagnetic SpectrumRadioShort
wavesMicro wavesInfraredUVX-raysGamma
raysCosmicrays
Electric PowerVisible
NIR SPECTROSCOPY
NIR2.65 x 10-19 J 7.96 x 10-20 J
12,500 cm-1 4,000 cm-1
800 nm 2,500 nm
NIR Applications in NIR Applications in Pharmaceutical IndustryPharmaceutical Industry
Principle
–Electromagnetic radiation in between 800 and 2500 nm is weakly absorbed by the X-H bonds of molecules. causing them to stretch. The wavelength of the radiation absorbed is characteristic of bond absorbing it.
Applications
–Quantitative analysis of multiple components in a sample and in pack quantification of drugs in formulation.
–Qualitative of a drug and quality control of complex excipients such as lactose and cellulose used in formulation.
NIR Applications in NIR Applications in Pharmaceutical IndustryPharmaceutical Industry
Strengths
–NIR radiation has good penetration properties and thus minimal sample preparation is required.
–Measurement results obtained within seconds Simultaneous measurement of several parameters.
–Non Destructive methods and no chemical waste.
Limitations
–Extensive method development is required before the technique can be used as a truly rapid analysis technique.
–Development of a method requires a specialist operator with computing knowledge.
–Instruments are expensive
NIR Applications in NIR Applications in Pharmaceutical IndustryPharmaceutical Industry
Advantages and Disadvantages
• DisadvantagesNot a “primary” method Some chemometrics knowledge requiredLess chemical information compared to IR/RamanInfluenced by physical properties of
sampleMany samples required for calibration
modelLong term support required (models, library, instrument etc)
• AdvantagesFast (5 - 30 sec. Typical)Little or no sample preparationSimple to operateNo waste, no pollutionMulti-component analysisAcceptable accuracy and precisionNon-destructive measurementMeasures both chemical and physical
propertiesSuitable for factory environmentRemote monitoring for ProcessReal-time chemical information from process
NIR Applications in NIR Applications in Pharmaceutical IndustryPharmaceutical Industry
NIRS Instrument:
NIR Applications in NIR Applications in Pharmaceutical IndustryPharmaceutical Industry
Solid fiber-optics probe
Semi-solid by transmissionLiquid by transmission
Tablet transmission
In-line measurement
Versatile measurement techniques by NIR
Liquid fiber-optics probe
Regulatory Requirements
The identity of a complete batch of starting materialscan normally only be ensured if individual samples are taken from all the containers and an identity test performed on each sample. It is permissible to sample only a proportion of the containers where a validated procedure has been established to ensure that no single container of starting material will be incorrectly identified on its label
NIR Applications in NIR Applications in Pharmaceutical IndustryPharmaceutical Industry
Sampling should be conducted at defined locations and by procedures designed to prevent contamination of the material sampled and contamination of other materials.
Regulatory Requirements
NIR Spectroscopy Technique
NIR technique can measure samples through PE/PP inliners in original containers in a sampling cabin.
NIR Applications in NIR Applications in Pharmaceutical IndustryPharmaceutical Industry
Key criteria for success in process applications
NIR Applications in NIR Applications in Pharmaceutical IndustryPharmaceutical Industry
- Proper probe placement for best sample spectrum- Keeping the probe clean- Ability to get samples for calibration- Robust calibration method/good reference method- Seamlessly transferable calibrations
• Reference samples• with reference values• and NIR spectra
Create a calibration
I.D.
+
How To Start with NIRHow To Start with NIR
NIR Applications in NIR Applications in Pharmaceutical IndustryPharmaceutical Industry
☺
Build a Calibrationand incorporate it in your application
• Type of Product: Drug A
• Parameter to determine: Moisture, %Assay, Etc …
• Sample through put: 10 samples per day or per year?
• Conc. range: 90.0-110.0% (for example)
• Reference method: Moisture: Karl-Fischer%Assay : HPLC
General Questions before starting
How To Start with NIRHow To Start with NIR
NIR Applications in NIR Applications in Pharmaceutical IndustryPharmaceutical Industry
Active Ingredient: HPLC
Accuracy of reference method
limits
accuracy of NIR calibration
(Note: Error of single NIR-measurement can be better than error of single ref. Measurement !)
Analysis with Reference MethodMoisture: Karl-Fischer
How To Start with NIRHow To Start with NIR
NIR Applications in NIR Applications in Pharmaceutical IndustryPharmaceutical Industry
Clarify these question,
then re-measure the reference samples again with NIR
Re-Measurement for Reference Spectra
• Select NIR measurement mode• Transmission, • Diffuse Reflectance, • Transflectance• Select measurement option• Liquid cell, • Solid cell (transflection adapter?) • Fiber optic probe, …• Sample prep required ?• Mixing for homogenization
How To Start with NIRHow To Start with NIR
♦ Required:• 50 - 100 samples for calibration• 20 - 50 samples for validation• “The more, the better!”
Samples must cover the whole range of expected variations
• Concentration range
• Origin
• Particle size distribution
Collection of Reference Samples
How To Start with NIRHow To Start with NIR
NIR Applications in NIR Applications in Pharmaceutical IndustryPharmaceutical Industry
Steps for NIR measurement
?!1. Define parameters (cell, scans / spectrum,…)
100%3. Collect samples with reference values
2. Measure NIR spectra of ref. samples
xx
x4. Build a calibration
5. Incorporate calibration in application
Use application for routine measurement ☺
How To Start with NIRHow To Start with NIR
NIR Applications in NIR Applications in Pharmaceutical IndustryPharmaceutical Industry
Qualitative
• Raw materials ID test• Bulk material (API) ID test• Finished product ID test• API within dosage forms• Blend homogeneity• Active/placebo ID in clinical
studies • Packaging materials ID test• Polymorphisms• Dissolution profiles• Isomers ID (optical or structural)
Typical NIR ApplicationsQuantitative
• Moisture content• Active ingredients in
tablet/capsule• Solvent composition• Particle size• Coating• Blend homogeneity (% and RSD)• Polymorphism• Hardness/Density etc.
NIR Applications in NIR Applications in Pharmaceutical IndustryPharmaceutical Industry
Raw Material Inspection :
NIR Applications in NIR Applications in Pharmaceutical IndustryPharmaceutical Industry
• Fundamentally chemically different compounds• Active Pharmaceutical Ingredient ( API )• Non Active Pharmaceutical Ingredient ( Excipients )• Dyes• Packaging material• Polymorphs• Isomers• Crystalline vs amorphous
The Benefits of Raw Material ID by NIR :
NIR Applications in NIR Applications in Pharmaceutical IndustryPharmaceutical Industry
• Reduced material movement – fewer accidents/reduced manpower
• Better control of material quality – tighter manufacturing controls
• Fewer lab delays – on-time production • Reduce testing time - higher throughput• Can move analysis to the warehouse• Fits into the FDA PAT initiative
Examples:
NIR Applications in NIR Applications in Pharmaceutical IndustryPharmaceutical Industry
Raw Material ID of Antiviral Drugs NevirapineLamivudine and Stavudine
NEVIRAPINE LAMIVUDINE STAVUDINE
FT-IR Separation of Antiviral Drugs NevirapineLamivudine and Stavudine
Examples: Identification Model
NIR Applications in NIR Applications in Pharmaceutical IndustryPharmaceutical Industry
NEVIRAPINE LAMIVUDINE STAVUDINE
Examples:
NIR Applications in NIR Applications in Pharmaceutical IndustryPharmaceutical Industry
Raw Material ID of Antiviral Drugs NevirapineLamivudine and Stavudine
Examples:
NIR Applications in NIR Applications in Pharmaceutical IndustryPharmaceutical Industry
Raw Material ID of Antiviral Drugs NevirapineLamivudine and Stavudine
FTNIR Separation of Antiviral Drugs NevirapineLamivudine and Stavudine
Examples: Identification Model
NIR Applications in NIR Applications in Pharmaceutical IndustryPharmaceutical Industry
In-line Raw material ID
NIR Applications in NIR Applications in Pharmaceutical IndustryPharmaceutical Industry
Quantitative analysis :
NIR Applications in NIR Applications in Pharmaceutical IndustryPharmaceutical Industry
• Moisture content• Active ingredients in tablet/capsule• Solvent composition• Particle size• Coating• Blend homogeneity (% and RSD)• Polymorphism• Hardness/Density etc.
Determination of Drug A and Two Excipients, in blending process, by fiber-optic probe
NIR Applications in NIR Applications in Pharmaceutical IndustryPharmaceutical Industry
Examples: Quantitative analysis
Determination of Drug A and Two Excipients, in blending process, by fiber-optic probe
NIR Applications in NIR Applications in Pharmaceutical IndustryPharmaceutical Industry
Examples: Quantitative analysis
Determination of Drug A and Two Excipients, in blending process, by fiber-optic probe
NIR Applications in NIR Applications in Pharmaceutical IndustryPharmaceutical Industry
Examples: Quantitative analysis
Diffuse ReflectanceHigh energyAssume homogeneitySurface measurementAnalyze Small portion of sampleFull NIR spectral range (400 to 2500 nm)
TransmissionLow energyheterogeneity !Bulk sample measurementAnalyze large portion of sampleLimited NIR spectral range
(600-1400nm)
NIR methods for tablet analysisNIR methods for tablet analysis
NIR Applications in NIR Applications in Pharmaceutical IndustryPharmaceutical Industry
- Raw Material ID- API Applications- Drying- Granulation- Blend Uniformity- Content Uniformity
Process Analytical Technology (PAT)
NIR Applications in NIR Applications in Pharmaceutical IndustryPharmaceutical Industry
- PAT initiative from FDA.- Aim: to improve the cost efficiency of manufacturing.- Understanding the process better.- Testing products as they are manufactured.- Minimizing the time for quality control and product verification.
- FDA: quality cannot be tested into products; it should be built-in or should be by design.
Process Analytical Technology (PAT)
NIR Applications in NIR Applications in Pharmaceutical IndustryPharmaceutical Industry
Current USFDA Definition of PAT
PAT in PAT in Pharmaceutical IndustryPharmaceutical Industry
A system for designing, analyzing and controlling manufacturing through timely evaluations (ie during processing), of critical quality and performance attributes of raw and in-process materials and processes, with the goal of ensuring final product quality.
US FDA Guidance for Industry “PAT- A Framework for Innovative Pharmaceutical Development, Manufacturing and Quality Assurance”, September 29, 2004.
- Utilizes a number of analytical techniques
- FDA encourages companies to use PAT in conjunction with new products
- Harmonization between FDA (USP), EMEA (EP), and Japanese authorities(JP)
- Pressure from pharmaceutical industry
- PAT will be the driving force for NIR
Process Analytical Technology (PAT)
PAT in PAT in Pharmaceutical IndustryPharmaceutical Industry
Related activities and guidances for NIR and PAT
PAT in PAT in Pharmaceutical IndustryPharmaceutical Industry
- ASTM E55 : Pharmaceutical Application of Process Analytical Technology
- Chaired by Don Marlowe, US FDA.- 140 members from pharmaceutical industry,suppliers, academia and regulatory.
- Will develop standards for PAT.- In-process revision USP <1119> General Information Chapter on NIR PF 29(6), Nov-Dec 2003.
- EMEA Guidance on the use of near infrared spectroscopy by the pharmaceutical industry.
- www.emea.eu.int
Example: NIR in Action (Solid Dosage)
Raw Material Testing
Dispensing
Wet granulation
Dry Compaction
Drying BlendingCapsule Filling
Tablet Compression
Coating
Unit
Ope
ration
NIR-Lab UseNIR-Lab Use
NIR- in Process Monitoring ControlNIR- in Process
Monitoring Control
NIR ID test & Assessment
NIR Chemical Imaging
NIR ID or
Assay
NIR Moisture , Density or hardness
NIR LOD (in-, on-
line) NIR
Homogeneity
NIR Potency
NIR coating
thickness/assay
Product
NIR Blend CU
NIR LOD
NIR Assay,moisture, hardness etc
PAT in PAT in Pharmaceutical IndustryPharmaceutical Industry
Future control philosophy with PAT
PAT in PAT in Pharmaceutical IndustryPharmaceutical Industry
Courtesy of: David Rudd PhD, Process Technology, GlaxoSmithKline Research and Development, UK
Manufacturing process
Control function
On-line monitoring of critical process
parameters
Process control
Process feed Process output
Closed loop control (process parameters only)
TemperatureTime
Pressureetc.
SummarySummary
Advantages of NIR-Spectroscopy
Simple : Almost no sample preparation required
Easy to operate: No special operator training required
Low operating costs : No solvent, No toxic waste
Nondestructive : Sample used for other purposes
Fast : Results with in minute
Versatile : Determination of several parameters