1. Dr. Katherine A. Bakeev B&W Tek, Inc Newark, DE USA September 24, 2013
Advantages of Handheld Raman in the Pharmaceutical Industry: Meeting PIC/S Requirements
Dr. Katherine A. Bakeev
B&W Tek, Inc
Newark, DE
USA
September 24, 2013
Why is the Pharmaceutical Industry interested in Raman?
Raman Technology
Data Integrity
Identification Method Development
Collecting Raman data
Challenges that Have Been Conquered
PIC/S: Unifying the Regulatory Perspective Globally.
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3. 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!
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4. 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.
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5. 2012: Japan and Korea applied for membership
PIC/S is the abbreviation and logo used to describe both the Pharmaceutical Inspection Convention (PIC) and the Pharmaceutical Inspection Co-operation Scheme (PIC Scheme) operating together in parallel.
The PIC Scheme commenced operating on 2 November 1995 in conjunction with PIC which had already been operating since 1970 (see "Background on PIC"). PIC/S became operational in November 1995.
The need to form the PIC Scheme became necessary when it was realised that an incompatibility between PIC and European law did not permit individual EU countries that were members of PIC to sign agreements with other countries seeking to join PIC. Only the European Commission was permitted to sign agreements with countries outside Europe, and the Commission itself was not a member of PIC.
Therefore, a less formal and more flexible cooperation scheme was developed to continue and enhance the work of PIC. Instead of being a legal treaty between countries (ie. like PIC), the PIC Scheme is a cooperative arrangement between Health authorities.
PIC and the PIC Scheme, operating together as PIC/S, provide an active and constructive co-operation in the field of GMP (Good Manufacturing Practice). The purpose of PIC/S is to facilitate the networking between participating authorities and the maintenance of mutual confidence, the exchange of information and experience in the field of GMP and related areas, and the mutual training of GMP inspectors.
PIC/S Applicants being assessed for membership as of 2013:
Brazil / ANVISA
Iran / MoH
Japan / PMDA, MHLW and Prefectures
South Korea / KFDA
Philippines / PFDA
United Kingdom / VMD (Vet)
Turkey
PIC/S Pre-applicants currently being assessed for pre-accession as of 2013:
Armenia / SCDMTE
Belarus / MoH
Uganda / NDA
Hong Kong applied for membership Aug 30, 2013
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2012: Japan and Korea applied for membership

6. 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
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7. 100% Raw Material Inspection
How can we rapidly perform 100% container identity testing?
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8. 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
CH3
Ar-H
S=O
CH2
C-O
Aromatic
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9. 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
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10. 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
Polystyrene
Vials
Amber and Clear Glass
Bags
Polypropylene (PP)
< 0.1mm
Polyethylene (PE), Low-Density Polyethylene (LDPE)
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11. Raman Spectra of Acetaminophen (Plastic Bag Effect)
No Significant Spectral Absorption from PE
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12. 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”
Variations in samples and sampling may include, for example:
Concentratio n of the Analyte of Interest
Material Suppliers
Water and Residual Solvent Content
Qualitative and / or Quantitative Variations in the Matrix (e.g. excipient grade, formulation)
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 Measuremen t
20 Jan EMA draft “ Guideline on the use of Near Infrared Spectroscop y (NIRS) by the pharmaceuti cal industry and the data requirement s for new submissions and variations”
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13. Define Measurement Parameters
Choose operation settings that will be used for collecting the data
Choose a sampling accessory appropriate to sample form
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14. 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
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15. Clear Results
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16. Analytical Instrument Qualification
USP <1058> Analytical Instrument Qualification
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17. Calibration Validation: PQ
Self check: by performing calibration validation using ASTM 1840 ref material: Polystyrene
Calibration Validation: PQ
Standard spectra of the following materials
Reference spectra on :
1. naphthalene (Mallinckodt #94848) 2. 1,4 bis (2-methylstyryl) benzene (BMB) (Aldrich #25,740-0) 3. sulfur (Aldrich #41,498-0) /50 (v/v) toluene/acetonitrile (Mallinckrodt Analytical Reagents) acetamidophenol (active ingredients of Tylenol) (Aldrich A730-2) 6. benzonitrile (Baker B883-07) 7. cyclohexane (Mallinckrodt Analytical Reagents) 8. polystyrene (Aldrich #18,243-5)
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18. NanoRam example
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19. NanoRam Method Development
The methods/libraries must be developed and can then be run on a routine basis after they have been validated
Method Development
Developer/Administrator
Measure 20 representative spectra
Build method based on PCA and establish threshold p-value (typically 0.05)
Test Method 
PC1
PC2
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20. NanoRam Identification Method
Sample Analysis
1. Access Method
2. Scan Sample
3. Identify Material
Operator/Developer/Admin
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21. Comparing Chemically Similar Materials
Potassium Carbonate
Potassium Carbonate Sesquihydrate
Raman spectra of potassium carbonate (red) and potassium carbonate sesquihydrate (blue).
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22. HQI : Library Searching
Library Spectrum
Sample
Potassium Carbonate
Potassium Carbonate Sesquihydrate
HQI=
HQI=
HQI=
HQI=
Difficult to get unambiguous results as the HQI is
>95 for both samples against library spectra
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23. Identification Method Using p-value
Sample
Potassium Carbonate
Potassium Carbonate Sesquihydrate
p-value =
0.9755
0.9825
0.9998
0.9262
p-value = x 10-4
2.990 x 10-4
2.597 x 10-4
6.153 x 10-5
4.077 x 10-5
p-value = 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 =
0.9534
0.9902
0.9919
0.9942
p-value > 0.05
0.001 <p-value≤ 0.05
10-6 <p-value≤ 10-3
0 <p-value≤ 10-6
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24. 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 )
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 patient
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25. 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.
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26. ICH Q2(R1) Analytical Method Validation
ICH Q2(R1) also call for:
SYSTEM SUITABILITY TESTING
System suitability testing is an integral part of many analytical procedures. The tests
are based on the concept that the equipment, electronics, analytical operations and
samples to be analyzed constitute an integral system that can be evaluated as such.
System suitability test parameters to be established for a particular procedure depend
on the type of procedure being validated. See Pharmacopoeias for additional
information.
ICH Q10 Pharmaceutical Quality System also addresses validation in a holistic manner
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27. 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
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28. Reports of Results
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29. Summary Increase analysis
Raman
Increase analysis
Cost reduction
Improve operations
Competitiveness
Summary
Raman has proven to be a promising tool to increase operational capabilities and reduce cost while providing rapid material identification.
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30. Thank you !
Dr. Katherine A. Bakeev B&W Tek Inc. 19 Shea Way Newark, DE 19713, USA
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31. Back up slides
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32. How Does Raman Compare?
In comparison to other vibrational spectroscopy methods, such as FTIR and NIR, Raman has several major advantages:
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33. Raman Related Documents (1)
Pharmacopeia
United States Pharmacopeia (USP34/NF29) General Chapter <1120> Raman Spectroscopy
European Pharmacopeia (Ph Eur 7.0) 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) …may utilize process analytical technology (PAT) tools e.g. near infrared spectroscopy (NIR) and Raman spectroscopy
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34. Raman Related Documents (2)
ASTM E (2007) Standard Guide for Raman Shift Standards for Spectrometer Calibration
ASTM E (2007) Standard Practice for Testing the Performance of Scanning Raman Spectrometers
ASTM E 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;
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35. Raman Applications in PharmaID
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
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36. NanoRam User Levels User Type User Type Symbol User Privileges
Operator
Select Method
Perform Material Identification
Select Operation Preset
Data Transfer
Developer
All of the above, plus:
Create /Edit Method
Create/Modify Operation Preset
Create/Modify Data Library
Administrator
Manage User Accounts
Create calibration files
Set system clock
Set password expiration
Create calibration file
Default password expiration period is 6 months
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37. Regulatory Standards Compliance
21 CFR Part 11 Electronic Records; Electronic Signatures
21 CFR Part Laser and Laser Systems
US Pharmacopeia <1120> Raman Spectroscopy
European Pharmacopeia Ch guidelines for Raman Spectroscopy- includes information on spectral library validation
ASTM (2007) Standard Guide for Raman Shift Standards for Wavelength Calibration
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38. Describe ID vs Investigation
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39. Raman has Greater Specificity than NIR: L-Aspartic acid
NIR spectra collected on Cary instrument – complements of Karl Norris, retired from USDA
Raman spectrum from B&W Tek iRaman PLus with 785 nm excitation
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40. Raman Scattering Raleigh Laser Raman 1,000,000 photons vs. 1
Unchanged Elastic Scattering
Laser
785 nm Excitation
Raman
Inelastic Scattering
1,000,000 photons vs. 1
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