near infrared spectroscopy applications in pharmaceutical ... · pdf...

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