advantages of handheld raman in the pharmaceutical industry: meeting pic/s requirements dr....

Advantages of Handheld Raman in the Pharmaceutical

Industry: Meeting PIC/S Requirements

Dr. Katherine A. BakeevB&W Tek, IncNewark, DE

USASeptember 24, 2013

www.bwtek.com 1Copyright 2013 B&W Tek, Inc.

Industry Trends and Requirements

• Pharmaceutical companies must meet worldwide PIC/S initiatives and regulations on Good Manufacturing Practice (GMP) for local Pharmacopeia and the US Food and Drug Administration

• PIC/S is unifying the regulatory perspective globally

• There has been a trend of increasing product contamination incidents, counterfeits, product recalls and facility shutdowns

• Companies must develop and implement improved analytics to check the identity, integrity and quality of ingredients and products by incoming material inspection

• Implementation of 100% testing of raw materials is coming!


What is PIC/S?• The Pharmaceutical Inspection Convention and Pharmaceutical

Inspection Co-operation Scheme (jointly referred to as PIC/S) are two international instruments between countries and pharmaceutical inspection authorities, which provide together an active and constructive co-operation in the field of GMP.

• PIC/S' mission is "to lead the international development, implementation and maintenance of harmonised Good Manufacturing Practice (GMP) standards and quality systems of inspectorates in the field of medicinal products.“

• PIC/S currently has 4 partners and 43 member countries with applications for Brazil, Japan, Korea and the United Kingdom under review.


GMP for Raw Material Identification

EU GMP and PIC/S GMP Guide

Chapter 5. Production

5.30 There should be appropriate procedures or measures to assure the identity of the contents of each container of starting material.

Annex 8 -Sampling of starting and packaging materials

2. Starting Materials

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 is performed on each sample. This means: 100% container testing


100% Raw Material Inspection

How can we rapidly perform 100% container identity testing?


Raman Spectral Information• Raman spectroscopy is a form

of molecular spectroscopy based on the scattering of light by molecules.

• A Raman spectrum is a molecular ‘fingerprint’ that provides structural information– Can identify materials based on

the spectrum

• Changes in intensity, frequency and peak bandwidth provide valuable information for quantitative and qualitative analysis

500 1000 1500 2000 2500 3000

Raman shift (cm-1)

(CH3)2C=O

CH3CH2OH

(CH3)2S=O

CH3CH2O2CCH3

C6H5CH3

C=O

C=O CH3

Ar-H

S=O

CH3CH2

C-O

CH3Aromatic


What Can Raman Do for You?Strong Raman Signal Active Pharmaceutical Ingredients Alcohols Antibiotics Antioxidants Buffers Coatings Diluents Emulsifiers Excipients Flavors Fragrances Lubricants Monomers and Polymers Polyatomic Inorganics Preservatives Solvents Vitamins

Weak Raman Signal Materials that are Dark in Color Highly Fluorescing Molecules Fillers/Binding Agents Glass Thin-walled Plastics Water

No Raman Signal• Black Materials• Metals• Mono-atomic ions


Raman Can Measure Through a Broad Class of Packaging

Bottles Thickness

Amber Glass < 2 mm

Clear Glass < 3 mm

High Density Polyethylene (HDPE) < 1 mm

Teflon FEP < 1 mm

Polystyrene < 1 mm

Vials

Amber and Clear Glass < 1 mm

Bags

Polypropylene (PP) < 0.1mm

Polyethylene (PE), Low-Density Polyethylene (LDPE)

< 0.1mm


Samples for Method Development

• The sample population for a qualitative or a quantitative procedure should cover all potential variation that may be encountered in routine production. (European Medicines Agency Draft Guidance on NIR; same approach applies for Raman spectroscopy)

• Variations in samples and sampling may include, for example:– Material Suppliers

– Process Variation (e.g. samples collected over an extended period)

– Sample Age and Positive Identification by Independent Means for Use in Library and Method Development

– Packaging and Sampling Accessories Used in Measurement

– Water and Residual Solvent Content

– Qualitative and / or Quantitative Variations in the Matrix (e.g. excipient grade, formulation)

20 Jan 2012 EMA draft “ Guideline on the use of Near Infrared Spectroscopy (NIRS) by the pharmaceutical industry and the data requirements for new submissions and variations”www.bwtek.com 12Copyright 2013 B&W Tek, Inc.

Define Measurement Parameters

• Choose operation settings that will be used for collecting the data

• Choose a sampling accessory appropriate to sample form


Tools for Identification and Verification

• Identification using a defined method with p-value (significance level) to verify material identification

• Investigation for unknown samples: HQI

• The HQI (Investigation mode) may be used for identifying unknowns and as an additional tool in method validation


Clear Results


Analytical Instrument Qualification

USP <1058> Analytical Instrument Qualification www.bwtek.com 16Copyright 2013 B&W Tek, Inc.

katherineb

may wanto reaplce this with ICH equivalent

Self check: by performing calibration validation using ASTM 1840 ref material: Polystyrene

Calibration Validation: PQ


http://www.chem.ualberta.ca/~mccreery/ramanmaterials.html

katherineb

update scree shot

NANORAM EXAMPLE


NanoRam Method Development

Method Development

• The methods/libraries must be developed and can then be run on a routine basis after they have been validated

Developer/Administrator

Measure 20 representative spectra Build method based on PCA and establish threshold p-value (typically 0.05)

Test Method

500060007000800090001000011000

Wavenumber cm-1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

Abs

orba

nce

Uni

ts

PC1

PC

2

PC1

PC

2


NanoRam Identification Method

Sample Analysis

1. Access Method 2. Scan Sample 3. Identify Material

Operator/Developer/Admin


Comparing Chemically Similar Materials

• Potassium Carbonate

• Potassium Carbonate Sesquihydrate

Raman spectra of potassium carbonate (red) and potassium carbonate sesquihydrate (blue).


HQI : Library Searching

Library Spectrum

SamplePotassium Carbonate

Potassium Carbonate Sesquihydrate

Potassium Carbonate HQI=99.5590 HQI=96.9013

Potassium Carbonate Sesquihydrate

HQI=97.5834 HQI=99.5908

Difficult to get unambiguous results as the HQI is >95 for both samples against library spectra


Identification Method Using p-value

Method

Sample

Potassium Carbonate

Potassium Carbonate

Sesquihydrate

Potassium Carbonate

p-value = 0.96390.97550.98250.99980.9262

p-value = 6.415 x 10-4

2.990 x 10-4

2.597 x 10-4

6.153 x 10-5

4.077 x 10-5

Potassium Carbonate

Sesquihydrate

p-value = 1.258 x 10-5

1.979 x 10-5

4.132 x 10-5

3.245 x 10-5

3.106 x 10-5

p-value = 0.99970.95340.99020.99190.9942

p-value > 0.05

0.001 <p-value≤ 0.05

10-6 <p-value≤ 10-3

0 <p-value≤ 10-6


Method Validation for Qualitative Analysis

• It is important to test methods to ensure the correct PASS of known good materials and the correct FAIL of materials that are known to be different from the material the method was developed for.

• Method Validation must include ensuring that there are not false positives or false negatives from the methods.

• Selectivity of qualitative methods should be challenged to ensure ongoing validity (EP 2.2.48)

• Validation requires risk assessment and should be done at a level commensurate with the risk that an incorrect result carries– Focus on minimizing possible harm to the patientwww.bwtek.com 24Copyright 2013 B&W Tek, Inc.

ICH Q7A GMP Guidance for Validation of Analytical Methods

(12.8)• Analytical methods should be validated • The suitability of all testing methods used should be verified under

actual conditions of use and documented. • Methods should be validated to include consideration of

characteristics included within the ICH guidances on validation of analytical methods. The degree of analytical validation performed should reflect the purpose of the analysis and the stage of the API production process.

• Appropriate qualification of analytical equipment should be considered before initiating validation of analytical methods

• Complete records should be maintained of any modification of a validated analytical method and should include the reason for the modification and appropriate data to verify that the modification produces results that are as accurate and reliable as the established method.


ICH Q2(R1) Analytical Method Validation


Data Management and Reporting• Need to have a

system of secure data management

• Records Reporting• Audit Trail• Calibration Validation

Reports• Account Management• Library Management

and Transfer


Reports of Results


Raman

Increase analysis

Cost reduction

Improve operations

Competitiveness

Raman has proven to be a promising tool to increase operational capabilities and reduce cost while providing rapid material identification.

Summary


THANK YOU !


Dr. Katherine A. BakeevB&W Tek Inc.19 Shea WayNewark, DE 19713, [email protected]

mailto:[email protected]

BACK UP SLIDES


How Does Raman Compare?In comparison to other vibrational spectroscopy methods, such as FTIR and NIR, Raman has several major advantages:


Raman Related Documents (1)Pharmacopeia•United States Pharmacopeia (USP34/NF29) General Chapter <1120> Raman Spectroscopy•European Pharmacopeia (Ph Eur 7.0) 2.2.48 Raman Spectroscopy•Pharmacopeia of the People‘s Republic of China (2010)- Raman Spectroscopy 拉曼光谱法指导原则

EMA Guidance – effective Oct 1, 2012•EMA/CHMP/QWP/811210/2009-Final Guideline on Real Time Release Testing (formerly Guideline on Parametric Release) 2012- …may utilize process analytical technology (PAT) tools e.g. near infrared spectroscopy (NIR) and Raman spectroscopy


Raman Related Documents (2)• ASTM E1840 - 96(2007) Standard Guide for Raman Shift

Standards for Spectrometer Calibration• ASTM E1683 - 02(2007) Standard Practice for Testing the

Performance of Scanning Raman Spectrometers• ASTM E2529 - 06 Standard Guide for Testing the Resolution of

a Raman Spectrometer

• US FDA Advancing Regulatory Science at FDA: A Strategic Plan (August 2011): Section 2. Develop new analytical methods:a) Investigate feasibility and value of using emerging and improved analytical technologies like Nuclear Magnetic Resonance (NMR), mass spectrometry, or near infrared or Raman spectroscopy for evaluating product quality of pharmaceutical agents, and evaluate whether these technologies should replace existing methods;


Raman Applications in Pharma• ID

– Identification Verification of and Identification of unknown raw materials This is the application for the NanoRam

• Quantitative Analysis – Quantitative determination of active substances in different

formulations• Polymorphism

– Supporting polymorphic screenings (polymorphs have different solubility rates, thereby impacting the effective dosing)

• Process – Real time quantitative analysis for process analytical

technology (PAT) such as blending, titration, reaction monitoring and polymorphic transition monitoring


NanoRam User LevelsUser Type User Type

SymbolUser Privileges

Operator Select MethodPerform Material IdentificationSelect Operation PresetData Transfer

Developer All of the above, plus:Create /Edit MethodCreate/Modify Operation PresetCreate/Modify Data Library

Administrator All of the above, plus:Manage User Accounts Create calibration filesSet system clockSet password expirationCreate calibration file


Regulatory Standards Compliance

• 21 CFR Part 11 Electronic Records; Electronic Signatures

• 21 CFR Part 1040.10 Laser and Laser Systems

• US Pharmacopeia <1120> Raman Spectroscopy

• European Pharmacopeia Ch.2.2.48 guidelines for Raman Spectroscopy- includes information on spectral library validation

• ASTM 1840-96(2007) Standard Guide for Raman Shift Standards for Wavelength Calibration


Describe ID vs Investigation


Raman has Greater Specificity than NIR: L-Aspartic acid


Raman shift (cm-1)

175. 283. 393. 501. 606. 710. 811. 910. 1014 1121 1224 1326 1425 1521 1617 1710 1802 1890 1978 2063 2147 2229 2310 2388 2466 2540 2615 2687 2757 2828 2895 2963 3028 3093 3155 3217 3277

0

5000

10000

15000

20000

25000

30000

35000

40000

45000

50000

55000

60000

65000

70000Raman spectrum of L-aspartic acid

Wavelength (nm)

1000 1046 1094 1142 1190 1238 1286 1334 1382 1430 1476 1524 1572 1620 1668 1716 1764 1812 1860 1908 1955 2003 2051 2099 2147 2195 2243 2291 2339 2387 2435 2481 2529 2577 2625

0

0.1

0.2

0.3

0.4

0.5NIR spectrum of L-aspartic acid

39

Raleigh

Unchanged Elastic

Scattering

RamanInelastic Scattering

Laser785 nm Excitation

1,000,000 photons vs. 1

Raman Scattering


advantages of handheld raman in the pharmaceutical industry: meeting pic/s requirements dr....

Documents

co ch

bakeev bw tek

membership slide

pics mission

raman spectrum

pharmaceutical industry

field of gmp

pics gmp guide chapter