Near Infrared Spectroscopy Applications in Pharmaceutical Industry

Transcription

1 Near Infrared Spectroscopy Applications in เภส ชกรน ต ส นแสนด Niti Sunsandee Pharmacist

2 Overview Principle and Application Regulatory requirements How to start with NIR Raw material analysis by NIR Quantitative NIR Applications Process Analytical Technology activities Summary

3 NIR SPECTROSCOPY Spectroscopy is the study of the interaction between matter and electromagnetic radiation Near Infrared Spectroscopy (NIR) is a type of vibrational spectroscopy The Electromagnetic Spectrum Cosmic rays Gamma rays X-rays UV Visible Infrared Micro waves Short waves Radio Electric Power Visible NIR MIR FIR NIR Microwave 2.65 x J 7.96 x J Energy [J] 12,500 cm -1 4,000 cm -1 Wavenumber [cm -1 ] 800 nm 2,500 nm Wavelength [nm]

4 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.

5 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

6 Advantages and Disadvantages Advantages Fast (5-30 sec. Typical) Little or no sample preparation Simple to operate No waste, no pollution Multi-component analysis Acceptable accuracy and precision Non-destructive measurement Measures both chemical and physical properties Suitable for factory environment Remote monitoring for Process Real-time chemical information from process Disadvantages Not a primary method Some chemometrics knowledge required Less chemical information compared to IR/Raman Influenced by physical properties of sample Many samples required for calibration model Long term support required (models, library, instrument etc)

7 NIRS Instrument:

8 Versatile measurement techniques by NIR Solid fiber-optics probe Liquid fiber-optics probe Tablet transmission Liquid by transmission Semi-solid by transmission In-line measurement

9 Regulatory Requirements The identity of a complete batch of starting materials can 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

10 Regulatory Requirements Sampling should be conducted at defined locations and by procedures designed to prevent contamination of the material sampled and contamination of other materials. NIR Spectroscopy Technique NIR technique can measure samples through PE/PP inliners in original containers in a sampling cabin.

11 Key criteria for success in process applications - 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

12 How To Start with NIR Create a calibration Reference samples with reference values and NIR spectra + I.D. Build a Calibration and incorporate it in your application

13 How To Start with NIR General Questions before starting Type of Product: Drug A Parameter to determine: Moisture, %Assay, Etc Sample through put: 10 samples per day or per year? Conc. range: % (for example) Reference method: Moisture: Karl-Fischer %Assay : HPLC

14 How To Start with NIR Analysis with Reference Method Moisture: Karl-Fischer 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!)

15 How To Start 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 Clarify these question, then re-measure the reference samples again with NIR

16 How To Start with NIR Required: Collection of Reference Samples samples for calibration samples for validation The more, the better! Samples must cover the whole range of expected variations Concentration range Origin Particle size distribution

17 How To Start with NIR Steps for NIR measurement 1. Define parameters (cell, scans / spectrum, )?! 2. Measure NIR spectra of ref. samples 3. Collect samples with reference values 100% 4. Build a calibration 5. Incorporate calibration in application x x x Use application for routine measurement

18 Typical NIR Applications Qualitative Quantitative 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) Moisture content Active ingredients in tablet/capsule Solvent composition Particle size Coating Blend homogeneity (% and RSD) Polymorphism Hardness/Density etc.

19 Raw Material Inspection : Fundamentally chemically different compounds Active Pharmaceutical Ingredient ( API ) Non Active Pharmaceutical Ingredient ( Excipients ) Dyes Packaging material Polymorphs Isomers Crystalline vs amorphous

20 The Benefits of Raw Material ID by NIR : 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

21 Examples: Raw Material ID of Antiviral Drugs Nevirapine Lamivudine and Stavudine NEVIRAPINE LAMIVUDINE STAVUDINE

22 Examples: Identification Model FT-IR Separation of Antiviral Drugs Nevirapine Lamivudine and Stavudine NEVIRAPINE LAMIVUDINE STAVUDINE

23 Examples: Raw Material ID of Antiviral Drugs Nevirapine Lamivudine and Stavudine

24 Examples: Raw Material ID of Antiviral Drugs Nevirapine Lamivudine and Stavudine

25 Examples: Identification Model FTNIR Separation of Antiviral Drugs Nevirapine Lamivudine and Stavudine

26 In-line Raw material ID

27 Quantitative analysis : Moisture content Active ingredients in tablet/capsule Solvent composition Particle size Coating Blend homogeneity (% and RSD) Polymorphism Hardness/Density etc.

28 Examples: Quantitative analysis Determination of Drug A and Two Excipients, in blending process, by fiber-optic probe

29 Examples: Quantitative analysis Determination of Drug A and Two Excipients, in blending process, by fiber-optic probe

30 Examples: Quantitative analysis Determination of Drug A and Two Excipients, in blending process, by fiber-optic probe

31 NIR methods for tablet analysis Diffuse Reflectance High energy Assume homogeneity Surface measurement Analyze Small portion of sample Full NIR spectral range (400 to 2500 nm) Transmission Low energy heterogeneity! Bulk sample measurement Analyze large portion of sample Limited NIR spectral range ( nm)

32 Process Analytical Technology (PAT) - Raw Material ID - API Applications -Drying - Granulation - Blend Uniformity - Content Uniformity

33 Process Analytical Technology (PAT) - 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.

34 Current USFDA Definition of PAT PAT in 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.

35 Process Analytical Technology (PAT) - 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 PAT in

36 PAT in Related activities and guidances for NIR and PAT - ASTM E55 : Pharmaceutical Application of Process Analytical Technology - Chaired by Don Marlowe, US FDA 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 EMEA Guidance on the use of near infrared spectroscopy by the pharmaceutical industry. -

37 Example: NIR in Action (Solid Dosage) PAT in NIR-Lab Use Use NIR ID test & Assessment NIR LOD NIR Blend CU NIR Chemical Imaging NIR Assay,moisture, hardness etc Unit Operation Raw Material Testing Dispensing Wet granulation Dry Compaction Drying Blending Capsule Filling Tablet Compression Coating Product NIR ID or Assay NIR- NIR-in in Process Monitoring Control NIR Moisture, Density or hardness NIR LOD (in-, online) NIR Homogeneity NIR Potency NIR coating thickness/ assay

38 Future control philosophy with PAT Process control Closed loop control (process parameters only) PAT in Control function On-line monitoring of critical process parameters Process feed Temperature Time Pressure etc. Manufacturing process Process output Courtesy of: David Rudd PhD, Process Technology, GlaxoSmithKline Research and Development, UK

39 Summary Advantages of NIR-Spectroscopy Simple : Fast : Versatile : Easy to operate: Nondestructive : Almost no sample preparation required Results with in minute Determination of several parameters No special operator training required Sample used for other purposes Low operating costs : No solvent, No toxic waste

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